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Rocky Mountain 
Spotted Fever 



The Henry E. Sigerist Series 
in the History of Medicine 

sponsored by The American Association for the History 
of Medicine and The Johns Hopkins University Tress 

The Development of American Physiology 
Scientific Medicine in the Nineteenth Century 
by W. Bruce Fye 

Save the Babies 

American Tublic Health Reform and the 
Trevention of Infant Mortality, 18^0-1919 
by Richard A. Meckel 

Politics and Public Health in Revolutionary 
Russia, 1890-1918 
by John F. Hutchinson 

Rocky Mountain Spotted Fever 
History of a Twentieth-Century Disease 
by Victoria A. Harden 



^ LIBRARY 

^ JAN 1 7 1991 

National Institutes of Health 

^ Rocky Mountain 
Spotted Fever 

History of a 

Twentieth-Century Disease 



Victoria A. Harden 



The Johns Hopkins University Press 
Baltimore and London 



The text for this book was prepared in the main part as 
an intramural project of the National Institute of Allergy 
and Infectious Diseases, National Institutes of Health. 

Foreword © 1990 The Johns Hopkins University Press 

Printed in the United States of America 

All rights reserved 

The Johns Hopkins University Press 

701 West 40th Street 

Baltimore, Maryland 21 211 

The Johns Hopkins Press Ltd., London 

The paper used in this publication meets the minimum requirements of Ameri- 
can National Standard for Information Sciences— Permanence of Paper for 
Printed Library Materials, ansi Z39. 48-1984. 

Library of Congress Cataloging-in-Publication Data 

Harden, Victoria Angela. 

Rocky Mountain spotted fever: history of a twentieth-century 
disease / Victoria A. Harden. 

p. cm. — (The Henry E. Sigerist series in the history of 

medicine) 
Includes bibliographical references. 
ISBN 0-8018-3905-X (alk. paper) 

1. Rocky Mountain spotted fever— History. I. Title. II. Series. 
RC182.R6H37 1990 

6i6.9'223— dc2o 89-48033 

CIP 



To the memory of 
John R. Seal 

who envisioned this history 

and to 

William L. Jellison 

who preserved so many of the documents on 
which it is based 



Contents 



List of Illustrations ix 
Foreword xi 
Preface xiii 

1 A Twentieth-Century Disease of Nature i 

2 A Blight on the Bitterroot 9 

3 The Beginning of Scientific Investigations 23 

4 Dr. Ricketts's Discoveries 47 

5 Tick Eradication Efforts, 1911-1920 72 

6 A Wholly New^ Type of Microorganism loi 

7 The Spencer-Parker Vaccine 119 

8 Spotted Fever outside the Rockies 147 

9 Dr. Cox's Versatile Egg 175 

10 Spotted Fever Therapy, 

from Sage Tea to Tetracycline 197 

11 Spotted Fever after Antibiotics 219 

12 Mysteries Explained, Mysteries Remaining 240 

Abbreviations 261 
Notes 265 
Note on Sources 347 
Index 359 



Illustrations 



Rash of Rocky Mountain spotted fever 4 

Known distribution of Rocky Mountain spotted fever, 
ca. 1900 13 

Louis B. Wilson and William M. Chow^ning 25 

Epidemiology of Rocky Mountain spotted fever in the Bitterroot 
Valley, Montana, 1902 27 

Rocky Mountain wood tick, male and female Dermacentor 
andersoni 3 o 

Charles Wardell Stiles 41 

Howard Taylor Ricketts 5 1 

Interior of Howard Taylor Ricketts's tent laboratory 52 
Ticks waiting on vegetation for a host 73 
Robert A. Cooley 78 

Flagging for ticks in the Bitterroot Valley 80 

Buildings in Victor, Montana, used as a laboratory by U.S. PubHc 
Health Service, 1911-16 83 

Thomas B. McClintic 87 

Lunsford D. Fricks 88 

Dipping vat in the Bitterroot Valley 92 

S. Burt Wolbach 104 

S. Burt Wolbach's drawing of the spotted fever organism in the 
tissues of infected animals 108 

Schoolhouse laboratory 121 

Roscoe R. Spencer and Ralph R. Parker 123 

William Edwin Gettinger, George Henry Cowan, and 
Albert LeRoy Kerlee 131 

ix 



Illustrations 



Tubes in the tick-rearing process 134 



Laboratory technician decanting Spencer-Parker vaccine into bottles 
for shipment, 193 1 134 

Rocky Mountain Laboratory, 1928 141 

Vaccinating against spotted fever, 193 1 145 

Rolla E. Dyer 149 

Dermacentor variabilis, vector of Rocky Mountain spotted fever in 
the eastern United States 151 

Distribution of Rocky Mountain spotted fever in the United States, 
1933 160 

Distribution of Rocky Mountain spotted fever in the United States, 
1941 166 

Letters and telegrams requesting bottles of the 
Spencer-Parker vaccine 171 

Ida A. Bengtson 176 

Herald R. Cox 179 

Technician harvesting yolk sacs from eggs infected with rickettsial 
organisms 182 

Rocky Mountain Laboratory during World War II 187 
Norman H. Topping 207 

Broad-spectrum antibiotics that cured Rocky Mountain spotted 
fever 214 

Deaths and ratios of cases to fatalities of Rocky Mountain spotted 
fever in the United States, 1940-70 220 

Reported cases of Rocky Mountain spotted fever per 100,000 
population, by year, in the United States, 1955-83 235 

Willy Burgdorfer 252 



Foreword 



One of the factors that attracted me to Rocky Mountain spotted 
fever was the rich historic lore of the subject. Years of collecting and 
studying the literature of the field confirmed my opinion that the stories 
expressed the emergence of science from the Western frontier. In this 
book, Victoria Harden conveys the history v^ith the vividness of the 
traditional storyteller and the care of the professional historian. What 
develops is the picture of the maturation of biomedical science in the 
United States. Scientists in the discipHnes of entomology, microbiology, 
pathology, medicine, and immunology have elucidated a novel infec- 
tious agent that normally resides in ticks. They began v^ith a prevalent 
public opinion that this dreaded plague v^as caused by drinking w^ater 
from melted snov^ and over the years reached a more accurate state 
of knowledge. Because of the dramatic severity of the clinical illness, 
work on these difficult organisms has continued. Rickettsiology has 
now overcome many of the technical obstacles that for so long inhibited 
progress. By employing molecular methods, the field has accelerated 
its pace and is now in the mainstream of microbiology. Genes have 
been cloned for important rickettsial components and specific func- 
tions. The power of science to make significant advances in rickett- 
siology has never been greater. 

Yet the number of institutions with research laboratories that are 
engaged in the investigation of Rickettsia rickettsii and its relatives are 
remarkably few. The medical importance of rickettsiae alone justifies 
considerably more effort. Rocky Mountain spotted fever is still a life- 
threatening disease for healthy persons who are engaged in outdoor 
activities. There are major pitfalls and deficiencies in both the clinical 
and laboratory diagnoses of Rocky Mountain spotted fever. The eti- 
ologic agent is firmly entrenched in nature and cannot yet be eradicated. 
Related rickettsiae frequently cause undiagnosed infections in southern 
Europe, Africa, and Asia. No effective vaccines are available. Medical 
treatment given late in the course of illness because of delayed diagnosis 
often fails to save the patient's life. 

In addition to the practical problems, there are many interesting 
scientific questions about rickettsiae that could lead to better under- 
standing of intracellular parasitism, pathobiology and immunobiology 



XI 



xii 



Foreword 



of intracellular bacteria, and endothelial pathophysiology. Numerous 
basic questions remain unanswered: How are rickettsiae maintained 
in nature? Is rickettsial infection pathogenic for the tick? What has 
prevented pathogenic R. rickettsii from occupying a greater proportion 
of the ecologic niche in ticks (less than o.i percent of the members of 
the major vector species of ticks contain disease-causing R. rickettsii)} 
How do the more prevalent nonpathogenic rickettsiae interfere with 
establishment of their pathogenic relatives? Why does the incidence 
and geographic distribution of disease appear to change during a period 
of time? What components of the immune system must be stimulated 
in order for it to resist infection or reinfection? How does the immune 
system rid the human host of an established infection? What is the 
composition of rickettsiae (e.g., what is the composition of the outer 
layer, putatively a slime layer?)? How do the rickettsial structural 
components mediate the various functions of the organism? How is 
virulence reactivated from its dormant state in ticks? How do host 
factors such as older age, male sex, the genetic condition of glucose- 
6-phosphate dehydrogenase deficiency, and possibly hemolysis lead to 
increased severity of illness? How do the rickettsiae cause human cell 
and tissue damage and disease syndromes? Do so-called nonpathogenic 
rickettsiae such as R. parkeri and R. rhipicephali infect humans, causing 
unrecognized syndromes? 

The number of fruitful lines of inquiry rapidly overwhelms the corps 
of rickettsiologists, whose ranks are already thin. The specialized cadre 
of scientists who know and understand rickettsiae must be expanded 
by educating more young scientists, and more funding is required for 
significant scientific progress. Rickettsiology has for years been viewed 
as archaic even as it has quietly opened new avenues of knowledge. 
Rickettsiologists have delved into topics such as the pathogenic roles 
of phospholipase and protease or the role of interferon-gamma in 
immunity to intracellular pathogens. They have solved such riddles as 
the cause of Legionnaires' disease, Lyme disease, and Potomac horse 
fever. During the next decade, rickettsiologists must continue to do 
basic laboratory investigation, teach others the science and historic 
lore, reach out to collaborate with colleagues abroad on the prevalent 
infections in Asia, Africa, and Europe. It is hoped that in the process, 
important new scientific advances will answer questions remaining 
from the early days of studies in the Bitterroot Valley of western 
Montana. It is even reasonable to expect better approaches to pre- 
vention, diagnosis, and treatment. The pace of progress may be ex- 
pected to reflect the support provided by public and private agencies. 

David H. Walker, M.D. 



Preface 



In 1984 I was invited to write a history of Rocky Mountain spotted 
fever for the National Institute of Allergy and Infectious Diseases 
(NIAID), the component of the National Institutes of Health (NIH) 
that traces its roots to 1 887, when federally sponsored medical research 
began. Since 1902, NIAID and its antecedent laboratories in the U.S. 
Public Health Service have supported research on Rocky Mountain 
spotted fever. The late John R. Seal, in 1984 deputy director and 
formerly director of intramural research, was the project's initial spon- 
sor within the institute. He believed that a history of this disease would 
contribute to the understanding of twentieth-century medicine and 
medical research. The project gained the support of NIAID director 
Richard M. Krause and of his successor, Anthony S. Fauci, and was 
placed within the NIH intramural research program. I began the work 
under Kenneth W. Sell, intramural director, who framed the assignment 
in broad terms and provided support services for the research. His 
successor, John I. Gallin, continued these policies and graciously ex- 
tended my deadline so that I might participate in preparations for the 
NIH centennial observance. 

Although the U.S. Public Health Service was not the only agency 
that contributed to the diagnosis, prevention, and cure of Rocky Moun- 
tain spotted fever, it has played a key role throughout this century. 
Because spotted fever occurs only in the western hemisphere — but not 
exclusively in the Rocky Mountain region, as its name implies— it held 
particular interest for investigators in the United States from the time 
it was first differentiated from other fevers. During the early decades 
of the twentieth century, much of the work on spotted fever was 
conducted at laboratories in the Bitterroot Valley of western Montana, 
where the disease was particularly virulent. A laboratory building 
initially constructed in 1928 by the state of Montana subsequently 
became the Rocky Mountain Laboratory (RML) of NIAID. Fortu- 
nately for the historian, many of the investigators at the RML kept 
meticulous records and saved their correspondence. In conjunction 
with documents at other institutions and with the published scientific 
Uterature, these records provided a rich archival source for the prep- 
aration of this history. During the course of the project, many state 



xiii 



xiv 



Preface 



and federal records at the RML were transferred to institutions where 
they will be preserved and made available to other scholars. The dis- 
position of these records is discussed in the Note on Sources. 

During the years of research for and writing of this book, I have 
incurred debts to many people, especially in Montana and at the NIH 
in Bethesda, Maryland. These included scientists, administrators, lab- 
oratory support staff, archivists, librarians, other historians, and lay 
persons whose lives have been touched by Rocky Mountain spotted 
fever. Many of these people are acknowledged in the Note on Sources, 
but doubtless I have not listed every one. I am grateful to all who took 
time from their schedules to enhance my understanding of this disease. 

Special thanks are due to Carolyn Brown's staff at the NIH library, 
who filled an astronomical number of requests for copies of papers 
and interhbrary loan books. Betty Murgolo, especially, went to great 
lengths to locate obscure but key sources. John Parascandola, chief of 
the History of Medicine Division, National Library of Medicine, and 
his staff, especially the curator of modern manuscripts, Peter Hirtle, 
also proved most helpful in suggesting relevant documents from their 
rich manuscript collections. Lois South in the Judicial, Fiscal, and Social 
Branch of the National Archives and Records Administration provided 
knowledgeable guidance to records in the collections of the U.S. Public 
Health Service and of the NIH. Archivists and librarians at the Mon- 
tana State Archives in Helena, Montana, and at the Renne Library of 
Montana State University in Bozeman, Montana, facilitated my search 
through their holdings. Archivist Richard Popp in the Department of 
Special Collections, Joseph Regenstein Library, University of Chicago, 
kindly assisted me in obtaining copies of the Howard Taylor Ricketts 
Papers. Carolyn Kopp, university archivist at the Rockefeller Univer- 
sity, similarly provided key materials from the Hideyo Noguchi Papers. 
Citations from these collections are used by permission of the Uni- 
versity of Chicago and of the Rockefeller University. 

Because of the key role of the Rocky Mountain Laboratory in spotted 
fever research throughout the twentieth century, I made extensive use 
of materials held at the RML library and at the Ravalli County His- 
torical Society. Many people in the Bitterroot Valley told me of their 
experiences and suggested other sources of information, but four peo- 
ple in Hamilton extended extraordinary assistance. Erma Owings, 
archivist at the Ravalli County Historical Society, helped in numerous 
ways as I researched this remarkable collection of county documents. 
William L. Jellison, a retired entomologist from the laboratory, active 
local historian, and curator of spotted fever artifacts, led me to records 
he had preserved from destruction, showed me historically important 



Freface 



XV 



sites in the valley, introduced me to many long-term residents who 
remembered the early days of spotted fever, and made helpful sugges- 
tions for improving the manuscript. Robert N. Philip, a former epi- 
demiologist at the laboratory, offered me his encyclopedic know^ledge 
of w^estern Montana and the fruits of his ow^n extensive research on 
spotted fever. His criticism of the manuscript proved invaluable. Fi- 
nally, Leza S. Hamby, Hbrarian at the laboratory, not only filled my 
every request for information but also made arrangements for me to 
see firsthand a dipping vat used to combat spotted fever early in the 
century. In addition, she alw^ays extended warm hospitality during my 
research trips to the valley. 

Among the numerous scientists and physicians to whom I accrued 
debts, special thanks must go to all whom I interviewed. Named in 
the Note on Sources, these people often became my patient teachers 
as I struggled to master a portion of the intricacies of microbiology, 
entomology, and immunology. Another dimension was added to my 
research when David H. Walker, then in the Department of Pathology 
at the University of North Carolina, School of Medicine at Chapel 
Hill, and now chairman of the Pathology Department at the University 
of Texas Medical Branch at Galveston, introduced me to the group of 
researchers in Palermo, Sicily, who are investigating Rocky Mountain 
spotted fever's rickettsial relative, boutonneuse fever. During a trip I 
made to Italy for a related research project, Serafino Mansueto, Giu- 
seppe Tringali, and Vittorio Scaffidi extended hospitaHty, recounted 
their research strategies, and made it possible for me to observe a case 
of boutonneuse fever. 

Once written, the manuscript received critical review from a variety 
of scientists and historians. Willy Burgdorfer, Eugene P. Campbell, 
James A. Cassedy, Alan M. Cheever, Robert Edelman, William Jordan, 
Richard A. Ormsbee, Margaret Pittman, Norman H. Topping, David 
H. Walker, and Charles L. Wisseman, Jr., read one or more chapters. 
Saul Benison, William L. Jellison, David B. Lackman, Robert N. Philip, 
and James Harvey Young read the entire manuscript. I am greatly 
indebted to each of them, whose suggestions significantly improved 
the accuracy and clarity of the book. Any errors that remain are mine 
alone. 

I must also gratefully acknowledge many other members of the 
NIAID and NIH staffs in Bethesda who extended themselves to assist 
me in various ways. Mary Ann Guerra provided essential administra- 
tive support throughout the project. Patricia Randall and her associates 
in the NIAID Public Information Office, especially Karen Leighty and 
Judy Murphy, proved most knowledgeable about recent institute his- 



xvi 



Preface 



tory and directed my attention to many internal files and pictures. 
Rurik Fredrickson, Harriet R. Greenwald, and Rhoda Laskin provided 
technical assistance during the course of the project. Rochelle Howard 
prepared computerized files of NIAID rickettsial grants and of a col- 
lection of photographs relating to this project. Joanie Shariat vetted 
the manuscript with skill and tact. 

Once in production, the book received careful attention from several 
members of the staff at Johns Hopkins University Press. Particularly 
I would like to thank executive editor Henry Y. K. Tom for his support 
and patience in bringing this manuscript to publication. 

Finally, I am grateful to my family, who never failed in their en- 
couragement of this project, even when my research files and draft 
manuscripts threatened to engulf the house. My husband, Robert L. 
Berger, proved to be an excellent research assistant as well as my first 
critical reader and a continuous source of moral support. 



Chapter One 



A Twentieth-Century 
Disease of Nature 

The unwritten history of the investigational work in connection with Rocky 
Mountain spotted fever, if written, would read like a romance. 

William Forlong Cogswell, ca. 1930 



Some diseases have been known to human beings for eons. Epilepsy, 
for example, was well recognized by the ancients, who called it the 
falling sickness because of its sudden seizures. Other diseases are quite 
new, acquired immunodeficiency syndrome, or AIDS, being perhaps 
the most recent example. Many diseases have come into or gone out 
of existence according to conceptual models that guided the medical 
communities of specific societies. Dropsy was a recognized clinical 
entity in the eighteenth century, but today it no longer exists as a 
distinct disease, its swelling of the tissues being viewed rather as a 
symptom of several different pathological conditions. Rocky Mountain 
spotted fever, the subject of this book, may thus be termed a twentieth- 
century disease. It was not recognized as a distinct clinical entity until 
just before the turn of the century, and nearly all of the efforts to 
understand and combat it have been made within this century. 

Rocky Mountain spotted fever is one of a group of maladies known 
as diseases of nature. The pathogenic organisms that cause these ill- 
nesses normally inhabit ticks, mites, fleas, mosquitoes, small rodents, 
and other wild animals. Malaria and bubonic plague are two other 
well-known members of this group. Human beings are usually acci- 
dental intruders into the natural cycles of these organisms that oth- 
erwise exist silently in nature. Because human beings are not a part 
of the organisms' biosystems, moreover, they often suffer more severely 
from infections of this group than do arthropod and mammaUan hosts. 

One subgroup of the diseases of nature is known today as the 
rickettsial diseases. They are caused by extremely small bacteria that 
have the peculiar characteristic of conducting their life processes inside 
the cells of their hosts— a property more generally associated with 
viruses. Measured in microns, a unit equal to one ten-thousandth of 



I 



2 



Rocky Mountain Spotted Fever 



a centimeter, rickettsiae take on three primary forms: spheres about 
0.3 microns in diameter; short rods 0.3 by i.o microns long; and thin 
rods about 2.0 microns long. In contrast, the cholera vibrio measures 
1.5—5 microns long, and the rods of the anthrax bacillus, the first 
pathogenic bacterium identified because of its large size, are 5-10 
microns long.^ The rickettsiae of spotted fever normally inhabit ticks, 
those of murine typhus hve in fleas, and the agents of rickettsialpox 
and tsutsugamushi are found in mites. Only one of the rickettsial 
diseases, in fact, has adapted to human beings as its hosts, and it is 
transmitted from one infected person to another via the body louse. 
This disease is classic, epidemic typhus, which is also notew^orthy as 
the only rickettsial disease recognized in the western world long before 
the twentieth century.^ 

As the rickettsial diseases were differentiated, they were divided into 
three groups: the typhus group, the spotted fever group, and the tsutsu- 
gamushi group, the last being a single disease hmited to Asia and the 
Pacific islands. In addition, diseases known as Q fever and trench fever 
have generally been associated with the rickettsial diseases, but each 
has exhibited sufficient differences from the other rickettsial diseases 
to be classified in a separate genus. Members of the spotted fever 
group, which includes Rickettsia rickettsii, the organism that causes 
Rocky Mountain spotted fever, are responsible for similar but not 
identical diseases scattered across the world. All are transmitted by 
ticks, except for the rickettsia that causes rickettsialpox, a mild, mite- 
borne disease that was initially confused with chickenpox. Each spotted 
fever group rickettsia, moreover, seems to have evolved its distinc- 
tiveness as have many animals and plants— through geographical iso- 
lation—for these organisms are found in "islands" of infection in 
particular locations. As one early researcher noted, "spotted fever is 
a 'place' disease, being definitely hmited to a certain locality."^ 

In widespread areas of Africa, in India and Southeast Asia, and in 
regions of Europe and the Middle East adjacent to the Mediterranean, 
Black, and Caspian sea basins, close relatives of R. rickettsii, most 
commonly Rickettsia conorii, cause relatively benign diseases similar 
to spotted fever. The names given these diseases also reflect the localities 
where they are known: Marseilles fever, South African tick typhus, 
Kenya tick typhus, and Indian tick typhus. Another member of the 
group, Rickettsia sibirica, produces a similarly mild disease, usually 
known as North Asian tick typhus or Siberian tick typhus. Its habitats 
are Siberia and many of the Asiatic republics of the Soviet Union, 
various islands of the Sea of Japan, Mongolia, Pakistan, and possibly 
Czechoslovakia. One other geographic area in which a closely related 



A Twentieth -Century Disease of Nature 



3 



disease is known to exist is the Queensland area of Australia. Caused 
by Rickettsia australis, this type of spotted fever is known as Queens- 
land tick typhus. 

Rocky Mountain spotted fever itself may be said to be an all- Amer- 
ican disease, because its causative organism is found only in the western 
hemisphere— North, South, and Central America. Transmitted by sev- 
eral different ticks that flourish in each ecological area, R. rickettsii 
causes a disease that has been known by the local names Sao Paulo 
typhus, Tobia petechial fever, Choix fever, American spotted fever, 
and New World spotted fever. Because it was first identified in the 
Rocky Mountain region of North America, however, its oldest ap- 
pellation was Rocky Mountain spotted fever. Later, when it was rec- 
ognized in other areas of the hemisphere, many scientists argued that 
such a provincial designation should be replaced with a more precise 
name, such as tick-borne typhus, but their proposals came too late. 
The name of the disease had become fixed in both public and medical 
minds, despite the unfortunate consequence that the risk of infection 
outside the Rocky Mountain region was thus masked. Recognized in 
the United States, western Canada, western and central Mexico, Brazil, 
Colombia, Panama, and Costa Rica, spotted fever varies in virulence 
from place to place. The reason for this variation remains unknown. 
Spotted fever may exact a mortality as high as 70 percent or as low 
as 5 percent. On an average, if left untreated, it will kill just over 20 
percent of its victims. Of all infectious diseases, spotted fever is one 
of the most severe, and it ranks as the most perilous of all rickettsial 
infections in the United States."^ 

Victims of Rocky Mountain spotted fever display variations of a 
closely related set of symptoms. A week or two after the patient has 
been bitten by a tick, the disease begins to manifest itself. The onset 
may be sudden or may be preceded by a few days of general malaise, 
after which the symptoms become more dramatic. The first sign is 
often a splitting headache— frequently described as the worst ever 
encountered by the victim— accompanied by pains in the back, joints, 
and legs. Light is painful to the eyes, and a stiff neck sometimes leads 
physicians to suspect meningitis. The spotted fever victim's temperature 
rises rapidly to 102° to 104° R The patient is usually restless, cannot 
sleep well, and frequently suffers from periods of delirium. Occasion- 
ally, the initial symptoms of spotted fever may mimic appendicitis or 
the common cold, making diagnosis difficult. 

As the infection progresses, the rickettsial organisms multiply within 
the endothelial cells that line the victim's capillaries. These cells even- 
tually swell, some burst, and by the third or fourth day of recognizable 




The rash of Rocky Mountain spotted fever covers the entire body, includ- 
ing the palms of the hands and the soles of the feet. Because so few diseases 
exhibit such an extensive rash, it is considered diagnostic in conjunction 
with high fever and history of exposure to ticks. (Courtesy of Eugene P. 
Campbell and used by permission of Norman H. Topping.) 



illness, blood begins to seep through tiny holes in the capillary walls. 
These hemorrhages cause the characteristic spots of the disease, which 
often look like the rash of measles and can be felt as slightly raised 
areas under the skin. They appear first on the wrists and ankles, 
spreading later to the limbs, the trunk and the face. Unlike the rash 
of some other rickettsial diseases, the spots of Rocky Mountain spotted 
fever often appear on the palms of the hands and the soles of the feet. 
Since only a few diseases produce this symptom, it is often considered 
a definitive diagnostic sign. 

If left untreated, most patients will recover from their illness within 
two weeks. Just over 20 percent, however, especially people over forty 
years old and those with existing medical problems, will die from their 
infections. In a few cases, the disease is fulminant, killing its victim 
within a few days of onset, often before the characteristic rash has 
appeared. 

That Rickettsia rickettsii is so well adapted to life in its tick host 
indicates a symbiotic relationship that has evolved over eons. This 



A Twentieth -Century Disease of Nature 



5 



suggests that spotted fever probably struck human victims long before 
it was distinguished as a separate disease. Recently, in fact, William 
D. Tigertt has argued that a 1759 epidemic in North Carolina was 
probably caused by Rocky Mountain spotted fever/ Civil War diaries 
also contain some references to afflictions that may have been spotted 
fever, such as seasonal occurrences of "black measles" chronicled by 
a nurse stationed near Cairo, Illinois.^ Because Rocky Mountain spot- 
ted fever remained undifferentiated from other fevers identified by 
similar names and symptoms until the late nineteenth century, however, 
historical inquiry into earlier periods is limited to speculation. The 
story of Rocky Mountain spotted fever may thus be said to begin with 
the description of a peculiar affliction recorded by pioneers traversing 
the trails across the North American west. Research on the disease 
certainly had its origins in a single place, the Bitterroot Valley of 
Montana. 

Although Rocky Mountain spotted fever was not identified until 
just before the twentieth century began, its louse-borne relative, epi- 
demic typhus fever, had plagued European populations for centuries. 
Almost always Hnked to conditions of human misery, typhus was 
known to accompany prisoners, sailors, armies, and refugees— popula- 
tions who, during cold weather, were likely to wear the same clothing 
day and night for weeks on end because of poor hygienic conditions. 
Because a widespread body rash, which does not spread to the face, 
also accompanies typhus, it, too, was often called spotted fever. In this 
book, however, I employ that term only as a synonym for Rocky 
Mountain spotted fever. 

Before I commence the story of Rocky Mountain spotted fever, a 
brief digression to review the history of epidemic typhus fever may be 
helpful, especially in understanding why spotted fever was not iden- 
tified as a distinct disease until the end of the nineteenth century. 
Hippocrates applied the word typhus^ from the Greek word meaning 
"smoky" or "hazy," to confused or stuporous states of mind frequently 
associated with high fevers. Accounts of ancient plagues, however, do 
not differentiate typhus from other epidemic fevers. The first descrip- 
tions of a disease that closely resembled typhus appeared near the end 
of the fifteenth century. In 1489-90, during the civil wars of Granada, 
Spanish physicians described a typhus-like disease that killed seventeen 
thousand Spanish soldiers— six times the number killed in combat with 
the Moors. In the early sixteenth century, a similar malady appeared 
among armies arrayed in Italy and in the Balkans. In 1546, Girolamo 
Fracastoro (Fracastorius), who had observed the Itafian epidemics, 
pubhshed the first clear description of what he termed a "lenticular 



6 



Rocky Mountain Spotted Fever 



or punctate or petechial" fever also characterized by headache and 
general malaise. Toward the end of the sixteenth century, typhus was 
also recorded in the Mexican highlands, where it killed more than two 
miUion Indians. It remains unclear, however, whether the disease was 
brought to the New World by Spanish explorers or, as some evidence 
indicates, was known to the Aztecs and some pre-Columbian Indians 
in Mexico.^ 

Typhus rose dramatically in early nineteenth-century Europe. In 
1812, Napoleon's catastrophic expedition to Russia was plagued by 
typhus. Between 18 16 and 18 19 a great epidemic of the disease struck 
seven hundred thousand people in Ireland, whose population was only 
six million. For several more decades, however, medical understanding 
of the disease remained confused. By the late eighteenth century, the 
medical nosologist Boissier de Sauvages had begun using the word 
typhus to describe the neurological symptoms of a particular disease, 
but few attempts were made to distinguish pathologically between 
typhus and typhoid fever, which also displayed a red rash. Even into 
the twentieth century, the link between typhoid and typhus was per- 
petuated in nomenclature. In many European countries, the former 
was known as typhus abdominalis and the latter as typhus exanthe- 
maticus.^ 

During the first half of the nineteenth century, researchers centered 
in the clinical schools of Paris, London, Dublin, and Vienna compiled 
detailed histories of diseases, which were correlated with gross path- 
ological lesions at autopsy. By this method they were able to distinguish 
more precisely among afflictions sharing similar symptoms, such as 
the many types of fevers from which people suffered.^ In 1837 a 
Philadelphia physician, WiUiam Wood Gerhard, who had studied the 
distinctive intestinal lesions of typhoid as a student of Pierre Louis in 
Paris, noted their absence in victims of typhus fever, which had been 
epidemic in Philadelphia the previous year. Gerhard's work, however, 
was not immediately embraced by physicians who clung to older the- 
ories of the unity of fevers. It was not until mid century that additional 
pathological and epidemiological research, especially by William Jen- 
ner and Austin Flint, convinced most American physicians that indeed 
typhus and typhoid were distinct disease entities. ^° 

The European revolutions of 1848 spawned typhus epidemics in 
Eastern Europe, as did African warfare in Ethiopia. During a partic- 
ularly severe outbreak of typhus in Upper Silesia, the German physician 
and politician Rudolf Virchow published a radical assessment of the 
epidemic that subsequently cost him his government post. Observing 
that the disease afflicted the poor, the uneducated, and the unclean, 



A Twentieth -Century Disease of Nature 



7 



Virchow called for democracy, education, and public health measures 
as the proper "treatment" of the epidemic. Although Virchow argued 
strongly for social reform as a means to benefit health, he also was in 
the vanguard of German scientists who believed that medicine would 
benefit from laboratory investigations. In research aided by improved 
microscopes, Virchow and other scientists focused on pathological 
changes in the tissues and cells to study the disease process. 

During the last quarter of the nineteenth century, such laboratory 
research culminated in the work of French chemist Louis Pasteur, 
German physician Robert Koch, and their associates, who identified 
specific microorganisms as the causes of particular infectious diseases. 
This new germ theory, when linked with the pathological changes 
documented for particular diseases, revolutionized the way physicians 
conceptualized infectious diseases. It also provided a framework in 
which rapid advances could be made in understanding afflictions such 
as typhus. Corollaries of the germ theory, which explained how mi- 
croorganisms were transmitted, provided a basis for active intervention 
programs to prevent diseases. Purifying water supplies reduced the 
incidence of waterborne diseases, for example. Crusades against insect 
vectors were also mounted to control such diseases as malaria and 
yellow fever. 

Rocky Mountain spotted fever was identified as a disease with symp- 
toms and a clinical course distinct from other fevers just as the germ 
theory was making its way across the Atlantic from Europe. Even 
though many American physicians and lay persons remained skeptical 
about the new theory, their response to diseases such as spotted fever 
was informed, if not initially guided, by its constructs. During ensuing 
decades, the germ theory transformed medical practice, fostered the 
growth of an international medical research establishment with its 
own professional dynamic, and established principles on which in- 
vestigational efforts were conducted. Furthermore, it furnished a con- 
text for lay persons to think about infectious diseases and altered their 
views of the role of governments in medical matters. In approaching 
the history of Rocky Mountain spotted fever, one must seek to un- 
derstand the interactions between these broad trends and the expe- 
rience of society with a single disease. What role did the profession- 
alization of science throughout the world play in strategies to 
understand and combat this disease? What can the experience with 
spotted fever tell us about the process of scientific discovery and ap- 
pUcation? How did communities respond to the presence of this disease 
in their midst? What role did they expect their governments to play, 
and how effective was political action against the disease? 



8 



Rocky Mountain Spotted Fever 



The history of Rocky Mountain spotted fever may thus serve as a 
lens through which we can view twentieth-century thought regarding 
infectious diseases and the apphcation of new concepts to research, 
diagnosis, prevention, and treatment. One of the early Montana leaders 
in the effort to combat spotted fever, quoted in the epigraph to this 
chapter, asserted that the story of research on spotted fever should 
read like a romance. In the following pages, I hope that some of the 
romance may be evident as well as an increased understanding of how 
science, medicine, and society in the twentieth century have responded 
to one particular disease of nature. 



Chapter Two 



A Blight on the 
Bitterroot 

Charles Draper, 25 years, of Kendall's lumber camp on the westside died at 
the Sisters Hospital on April 4 of that dread disease spotted fever, after a 
few days' illness. 

Obituary, Northwest Tribune, 1901 



The curved western border of the state of Montana somewhat re- 
sembles the profile of an Indian brave. Thrusting into the Idaho pan- 
handle like the nose of that brave is the spectacular Bitterroot Valley.^ 
Protected from the full force of winter storms by the rugged Bitterroot 
Mountains on the west and the more gentle Sapphire range to the east, 
the valley's flat bottomlands are the remains of an ancient lake whose 
beaches remain visible as bench lands on either side. Through the 
valley, which stretches approximately one hundred miles long and 
from eight to ten miles wide at an average elevation of thirty-five 
hundred feet above sea level, the Bitterroot River flows from south to 
north into the Clark's Fork of the Columbia River near Missoula. Not 
far away is the so-called Yellowstone hot spot, where the earth's molten 
interior rises close to the surface, producing geysers, hot springs, and 
boiling mud. Although less geologically active than Yellowstone, the 
Bitterroot Valley became known as a medical hot spot just before the 
twentieth century began. It was here that a mysterious disease, virulent 
Rocky Mountain spotted fever, claimed many lives and challenged 
researchers seeking to solve its riddle to formulate new concepts about 
the nature of infectious diseases. 

Until the last quarter of the nineteenth century, there were no ac- 
counts of any unusual disease in the Bitterroot, whose invigorating 
cHmate attracted first Indian and later white inhabitants.^ The Salish, 
or Flathead, Indians, who lived in the valley and ate the bitter roots 
of a pink spring wildflower from which the valley took its name, 
reported no special local affliction. Like most primitive peoples, the 



9 



lO 



Rocky Mountain Spotted Fever 



Salish interpreted disease as a magicoreligious process, in which a 
malevolent spirit, acting on its own or at the behest of an enemy of 
the sick person, brought suffering.^ The Indians did not make detailed 
diagnostic observations that could be used later as medical evidence, 
and their oral tradition precluded written records in any case. 

Before the arrival of whites, the Salish, like most other American 
Indians, were remarkably healthy. They were free from most diseases 
caused by airborne microorganisms because the cold, dry air of Mon- 
tana was inimical to airborne bacteria. Contagious diseases such as 
smallpox, diphtheria, scarlet fever, measles, and venereal ailments, 
which ravaged European cities, did not touch them. Since accidents 
and wounds sustained in warfare were common, however, the Salish 
had developed competency in setting fractures. Intestinal problems and 
rheumatic complaints, of which there were many, were usually treated 
by sweat baths or plunges into icy streams; sometimes a combination 
of these methods was used. Among Sahsh traditions was a general 
spring warning against entering certain canyons in the Bitterroot said 
to be inhabited by evil spirits. After the identification of virulent spotted 
fever, this admonition suggested that the Salish might have been fa- 
miliar with the disease, but later Indian testimony failed to confirm 
this. One of the earliest reports on spotted fever noted that "no au- 
thentic information" could be obtained linking the Indian superstition 
to the disease, "though many old residents, including Indians, white 
trappers, traders, and Catholic priests were consulted.'"^ 

Accounts of the periodic visits of non-Indians in the valley during 
the early nineteenth century, furthermore, are notable for the absence 
of any mention of a deadly disease. The most famous early visitors 
were members of the Lewis and Clark expedition, who traversed the 
valley in September 1805. Before embarking on their journey, Meri- 
wether Lewis and William Clark had been given medical instruction 
by respected physicians, including the distinguished Benjamin Rush. 
The explorers were advised to pay special attention to the health of 
the Indians they encountered.^ They recorded the presence of trachoma 
among the Columbia River Indians and the "calamity of bHndness" 
that had resulted from this disease.^ When they traveled through the 
Bitterroot, however, camping near the later towns of Grantsdale and 
Stevensville, the explorers did not record the presence of any feared 
local malady. In September the wood ticks that carry spotted fever are 
in estivation, or "summer hibernation," hence Lewis and Clark were 
not at great risk. On the return trip of the expedition the following 
year, Clark revisited the Bitterroot in early July — a time during which 
some ticks would probably still be active— while Lewis returned to 



A Blight on the Bitterroot 



II 



Saint Louis across northern Montana. Clark's path wound through 
the section of the Bitterroot where spotted fever was later shown to 
be most prevalent, yet he reported no unusual occurrences. The ex- 
periences of Lewis and Clark in the Bitterroot suggest three alternative 
scenarios with regard to spotted fever in the early nineteenth century: 
first, at this time virulent spotted fever was not widely spread through 
the Bitterroot; second, the disease existed, but its tick vectors were in 
estivation during both visits; and third, Lewis and Clark were simply 
lucky not to encounter the deadly fever. 

For several decades after Lewis and Clark's expedition, few other 
white visitors came to the Bitterroot. The number of travelers to other 
western areas was stimulated by the Mormon immigration to Utah in 
1847 and the discovery of the CaHfornia goldfields two years later. 
Many of these mid-century settlers and prospectors commented on 
various fevers encountered on the Oregon Trail in Wyoming, northern 
Utah, and southern Idaho. Bull fever, mountain fever, typho-malaria 
fever of the Rocky Mountains, black fever, blue disease, and spotted 
fever were all names reported. Although these diseases are difficult to 
diagnose retrospectively, some may have been cases of Rocky Moun- 
tain spotted fever. Most early observers, including U.S. Army physi- 
cians stationed at outposts in the region, described the diseases they 
encountered in terms of those with which they were familiar in the 
east. They assumed that these diseases had been "altered by chmate 
and altitude," changes that explained unusual clinical pictures.^ 

The first whites to live continuously in the Bitterroot Valley were 
neither prospectors nor settlers but rather Jesuit priests, who arrived 
in 1 84 1 at the request of the Sahsh. This unusual attraction of the 
Indians to white religion had developed through the Sahsh's contact 
with Canadian Indians. In the 1820s a band of Iroquois had left their 
homes on the Saint Lawrence River and migrated across the continent 
to the Bitterroot. The Salish welcomed the Iroquois as friends, even- 
tually intermarried with them, and rapidly adopted the Roman Cath- 
olic doctrines that the Iroquois had learned from French CathoHc 
priests in Canada. During the 1830s, "a desire to have some 'Black 
Robes,' in their midst" took possession of the Salish. Between 183 1 
and 1836, they dispatched three envoys to Saint Louis to petition the 
church for a priest to be sent to their tribe. This request was granted 
in 1840, and the following year two Jesuit missionaries, Gregory Men- 
garini and Pierre-Jean DeSmet, arrived to found Saint Mary's Mission 
in the north end of the valley, near the later site of the town of 
Stevensville. In 1845 ^ medically trained Jesuit, Anthony Ravalli, was 
sent to serve the Indians at Saint Mary's. He remained for five years 



12 



Rocky Mountain Spotted Fever 



until Saint Mary's was closed in 1850 because of a threatened attack 
from hostile Indian tribes. In 1867, the year after the mission was 
reopened, Ravalli returned and expanded his medical practice to in- 
clude white settlers who had migrated to the valley after the Civil War. 
Father RavaUi, after whom was named the county in which most of 
the Bitterroot Valley lies, was one of very few physicians available to 
valley residents until the mid 1880s. Many stories recount Ravalli's 
self-sacrificing medical practice, but none specifically mentions spotted 
fever as a problem with which he dealt.^ 

During the sixteen years that the Jesuits were absent from the valley 
between 1850 and 1866, white settlement commenced. As the priests 
departed, John Owen, a former army sutler and self-styled major, 
leased mission property for the construction of a trading post, which 
was quickly dubbed Fort Owen because of the walled stockade sur- 
rounding it. In the early 1860s, when gold was discovered in Montana, 
Owen profited from the sale of vegetables and flour to the mining 
camps. The gold rush also brought new settlers into Montana and the 
Bitterroot. In 1864 the brothers Harry and James Cohen settled in the 
valley with their wives, who became the first white women to establish 
residency in the Bitterroot.^ During the next decade many other families 
arrived and helped found towns along the river that resembled pearls 
on a string. Stevensville and Corvallis were estabUshed in 1864 and 
1868, respectively, and by 1880 there were more than a thousand 
white settlers living in the valley. Many new residents were probably 
seeking to avoid the social upheavals caused by the Civil War and 
Reconstruction, for a significant portion of them came from Kentucky, 
Georgia, and the Carolinas. Others migrated from Missouri, Quebec, 
and New Brunswick. These early settlers produced grain, engaged in 
lumbering on a small scale, and experimented with fruit orchards, 
especially apples. The first fruit trees were apparently planted in 1866, 
and after 1870, under the leadership of the brothers W. E. and D. C. 
Bass, apples became a commercial crop.^^ 

The increasing use of land in the Bitterroot for these economic 
pursuits eventually produced discord with the hunting-gathering way 
of life of the Salish. In 1871, President Ulysses S. Grant ordered that 
the Sahsh, along with the Nez Perce Indians who migrated annually 
through the valley, be removed to the Jocko Reservation in northern 
Montana. The following year. General James A. Garfield negotiated 
a treaty to this effect with two of the three Salish chiefs. Chief Chariot, 
son of Victor, for whom one of the valley towns was named, refused 
to sign. He won the right to remain in the Bitterroot until his death, 
but he and his followers were expected to live on small grants of land 




n 

-0 



r- t:^ 



T 



\ 



0 




^ I) 0 



Retrospective studies in the early twentieth century revealed that spotted 
fever had been encountered throughout the West during the late nineteenth 
century by prospectors and settlers. This map shows its known distribution 
about 1900. (Courtesy of the Rocky Mountain Laboratories, NIAID.) 



14 



Rocky Mountain Spotted Fever 



like white settlers. The Indians were not successful as farmers, hence 
in 1 89 1, Chariot decided to abandon the valley. Accompanied by a 
hundred other Salish who had remained in the valley, Chariot moved 
to the reservation, leaving the Bitterroot Valley wholly in the hands 
of whites. 

During this transition period, the white population of the Bitterroot 
swelled as construction of the Northern Pacific Railroad approached 
Missoula. After 1880, sawmills sprang up to supply railroad ties, sheep 
were grazed on the east side of the valley, and, when quartz deposits 
were discovered, an interest in mining developed. The Northern Pacific 
was completed to Missoula in 1883, and five years later a branch line 
was constructed up the Bitterroot as far as Grantsdale. As opposed to 
the rough wagon road along the river in 1870, the railroad provided 
businessmen in the valley an efficient conduit for transporting their 
goods to market. By 1890 there were eight sawmills in constant op- 
eration; two flour mills; more than thirty- three thousand sheep pro- 
ducing wool for shipment to commercial markets; a growing number 
of quartz, silver, and copper mines; and more than one-hundred thou- 
sand fruit trees, which came to make the valley known as the apple 
center of Montana. 

Lumbering operations were especially active during this period. In 
1887, for instance, one lumber mill near Lake Como was cutting ten 
thousand feet of lumber per day, and by 1890, one near Grantsdale 
produced forty thousand feet each day.^'* This was just the beginning 
of the boom, however, because railroads, mines, and other markets 
had an insatiable appetite for lumber. Sawmills provided jobs for 
hundreds of valley residents, and the bountiful forests of the Bitterroot 
seemed to offer an endless supply of trees. By 1896 lumbering oper- 
ations in the valley produced some sixty to seventy million feet of 
lumber each year.^^ 

Much of this massive deforestation took place on the west side of 
the valley, the site where virulent spotted fever was contracted. In 
recent years researchers have speculated about a relationship between 
the denuding of the valley's trees and the advent of virulent spotted 
fever. Robert N. Philip, an epidemiologist formerly at the Rocky Moun- 
tain Laboratory, has compiled extensive records about the history of 
the valley and the occurrence of the disease. He points out that the 
incidence of spotted fever "was vitally related to timber harvest and 
the opening of the west side woodlands to grazing and unwanted small 
mammal and tick infestation."^^ The scrub vegetation that replaced 
the forests was an ideal habitat for small rodents and their tick par- 
asites. Humans entering this area consequently ran an increased risk 



A Blight on the Bitterroot 



15 



of encountering infected ticks. This hypothesis offers a logical expla- 
nation for the apparently sudden appearance of the disease at the end 
of the century. Speculation about why spotted fever was more deadly 
in the Bitterroot than across the mountains in Idaho, on the other 
hand, focuses on a possible genetic mutation m the organism but 
remains a mystery. 

In 1889, Montana was granted statehood, and expansion in the 
Bitterroot continued unabated. Marcus Daly, the copper magnate of 
the Anaconda Mining Company, bought acreage in the valley for 
breeding his celebrated race horses. In 1 890, Daly established a sawmill 
near his propert}' and founded a town named after one of his agents, 
James W. Hamilton, for the mill hands. ^" Three years later most of 
the Bitterroot Valley was split off from Missoula County and named 
Ravalli Count}' after the venerated physician-priest. In 1898 the Ravalli 
Count}^ seat was moved from its original site in Stevensville to Ham- 
ilton. 

As the population of the Bitterroot increased during these two dec- 
ades of expansion, so did its need for medical attention. Some phy- 
sicians had moved into the valley after 1870, but w^ith under a thousand 
people scattered over its one-hundred-mile length, few stayed for very 
long, because a doctor had to engage in other pursuits as well as 
medicine to make a living. In 1880, for example, the Weekly Mis- 
soulian published this advertisement: "A good physician is much 
needed up the Bitter Root Valley. There are probably a thousand people 
on the Bitter Root, and, save the venerable Father RavaUi, there is no 
medical advisor the whole length of the Valley. It strikes us that a man 
who is willing to do a little farming or stock-raising in connection 
with his medical practice could reap a harvest in this localit)^ He should 
be a young man and willing to make hard rides occasionally."^^ 

In spite of the difficult conditions, this call for help was answered. 
By 1882 two physicians had accepted the challenge and estabhshed 
practices in the Bitterroot. One of them, R. A. Wells, was immediately 
charged with managing a smallpox epidemic. In 1884, Father Ravalli 
died, and the new^ doctors who took his place assumed the arduous 
task of dealing with the common infectious diseases against which no 
successful therapy was then available. In 1885, for example, a diph- 
theria epidemic claimed six Hves of its eight reported victims. Between 
1883 and 1885, fifn'-four Indians were buried, many of them young 
people, apparently victims of tuberculosis.^^ Typhoid was a recurring 
problem, primarily because of contaminated water at sawmills and 
mines. Smallpox epidemics flared annually because many people were 
not vaccinated, even though an efficacious vaccine was available. 



i6 



Rocky Mountain Spotted Fever 



During this period of settlement and growth, there were few reports 
of spotted fever cases. Before 1895 newspapers cited fifteen illnesses 
that might be construed as spotted fever, and a later official survey 
noted twenty-three cases certified by local physicians. A retrospective 
diagnosis made after the turn of the century marked 1873 as the year 
in which the first definite case of the disease was evident. The victim, 
identified only as "J.W.," lived near Woodside and died in May 1873. 
Since the attending doctor, who may have been John B. Buker, an 
Indian agent and a physician, had died by the time this inquiry was 
made, diagnosis was on the basis of testimony from the stricken man's 
relatives and neighbors who had seen later cases of the disease. 
Reports of spotted fever deaths first appeared in local newspapers in 
1882 and 1883. Diagnoses in these cases were never confirmed, how- 
ever, and they may in fact have been some other disease. 

Since there was no hospital in the Bitterroot until 1895, valley 
physicians transported their severely ill patients to Missoula. In 1873 
a French Canadian order of Roman CathoHc nuns, the Sisters of Char- 
ity of Providence, established the first hospital in Missoula, which was 
officially named Saint Patrick's Hospital but commonly called Sisters 
Hospital. Until 1889 it consisted of only one room. With the coming 
of the railroad, however, the Northern Pacific Beneficial Association, 
Western Division, Relief Fund was organized in 1882 with headquar- 
ters in Missoula. This organization, to which all Montana employees 
of the Northern Pacific belonged, erected the Northern Pacific Hospital 
in Missoula in 1884. Destroyed by fire in 1892, the hospital was rebuilt 
in 1893 expanded in 1901.^^ As spotted fever cases increased 
toward the end of the century, both hospitals cared for its victims. 

Many of the early physicians in the Bitterroot had studied medicine 
at respected schools in the midwest and east, including the Saint Louis 
Medical School, Jefferson Medical College in Philadelphia, Bellevue 
Hospital Medical College in New York, and the University of Virginia 
Medical School. Some of these doctors made a special effort to stay 
abreast of the latest developments in medicine in order to incorporate 
the new techniques into their practices. Keeping up with new medical 
discoveries was no easy task in the 1880s, for during this decade the 
concept of infectious diseases was being revolutionized. In the mid 
1870s, Louis Pasteur, a French chemist, and Robert Koch, a German 
physician, had demonstrated that bacteria caused anthrax, and their 
findings launched a heady period of searching for other microorganisms 
that might be the cause of dread epidemics. During the 1880s bacteria 
were identified as the culprits in typhoid fever, leprosy, tuberculosis, 
diphtheria, tetanus, pneumonia, and bubonic plague, among others. 



A Blight on the Bitterroot 



17 



Once bacteria had been demonstrated as the causes of particular 
diseases, scientists also sought to understand how they were trans- 
mitted from one sick person to another. By the end of the century, 
water, milk, insects, and human carriers had been implicated as po- 
tential routes for the spread of disease/^ Some diseases, moreover, 
responded to treatment with the blood serum of recovered victims, 
and others were found to be preventable by vaccines made from killed 
or attenuated organisms. It was, in short, a period during which dis- 
coveries piled quickly on top of one another and the tree of knowledge 
was ripe for picking. For young physicians and scientists, medical 
research offered challenging intellectual problems, an opportunity to 
contribute directly to the welfare of the world, and even the possibility 
of great celebrity for themselves. 

The bacteriological discoveries also provided new inspiration to the 
pubhc health or sanitary movement that had evolved in the United 
States primarily since the Civil War. This movement had been divided 
philosophically between those who attributed the cause of infectious 
diseases to specific agents and others who believed that poisonous 
vapors, known as miasmas, rose from contaminated earth to bring 
disease. The former group, called contagionists, had long advocated 
quarantine when disease was present, while the latter, known as an- 
ticontagionists, called for strict sanitary measures designed to remove 
the contamination that gave rise to miasmas. With the advent of 
bacteriology, these two views could be reconciled, and it appeared that 
pubhc health programs based on scientific principles might indeed rid 
the cities of the world of recurring plagues. 

In the United States, state and local public health boards, which had 
evolved since the Civil War in urban eastern areas, began to multiply 
in other areas of the country. By 1887 the town of Missoula had 
created a board of health, and in March 1896 the Ravalli County 
Board of Health was established in the Bitterroot Valley, with Samuel 
W. Minshall as first chairman. In 1902, moreover, the U.S. Congress 
also fostered the development of public health by providing for an 
annual meeting of state and territorial health officers with the surgeon 
general of the U.S. Public Health and Marine Hospital Service. ^° It 
was hoped that the exchange of information at this meeting would 
enhance the attack on disease throughout the nation. 

On 15 March 1901, Governor Joseph K. Toole signed an act passed 
by the Legislative Assembly creating a board of health for the state of 
Montana. As in other states, the Montana State Board of Health's 
charge was broad. It was to investigate epidemics; to suppress nuisances 
(that is, to see that unpleasant surroundings were cleaned up); to 



i8 



Rocky Mountain Spotted Fever 



attempt to determine the influence of locality, climate, employments, 
and habits on the health of the people; and to cooperate with local 
boards of health. Unfortunately, the budget allocated for this work 
was only two thousand dollars a year, its small size another charac- 
teristic shared with many other state boards of health. William Treacy 
of Helena was elected president, and Albert F. Longeway of Great 
Falls, having just completed a year as president of the Montana Medical 
Association, was named secretary, the officer charged with enforcing 
the board's poHcies. Other members of the board were two physicians, 
James L. Belcher of Townsend and H. J. Loebinger of Butte; J. M. 
Robertson, a civil engineer from Bozeman; and the governor and 
attorney general as ex officio members.^ ^ 

It was during this period, when medicine and public health looked 
forward optimistically to becoming truly scientific, that the problem 
of Rocky Mountain spotted fever was first addressed. Although the 
number of cases was increasing, paralleling the growth of the Bitter- 
root's population, only gradually was the disease given the uniform 
designation spotted fever. Many early cases were called black measles, 
probably because measles was widely known as an early childhood 
affliction, and spotted fever, with a similar rash, seemed to be a ma- 
lignant form of it. The designations black typhus fever and blue disease 
occasionally appeared, and often the disease was called black fever or 
simply fever.^^ Physicians reporting on it frequently called it typhoid 
pneumonia, measles, and cerebrospinal meningitis, because of the 
symptoms it shared in common with these better-known maladies— 
a stiff neck, headache, high fever, and rash.^^ Known to occur in the 
spring, the affliction most frequently struck residents or visitors on the 
west side of the Bitterroot River and was most often reported in the 
northern section of the valley, which overlapped Ravalli and Missoula 
counties. 

Spotted fever was not confined to the Bitterroot Valley alone, but 
it was known to be considerably milder in other locations. The first 
pubhshed report on the disease, in fact, was made in 1896 by Major 
Marshall W. Wood, a U.S. Army physician stationed in Boise, Idaho. 
A native of Watertown, New York, who had studied medicine at Rush 
Medical College in Chicago, Wood mentioned in one of his monthly 
reports the "prevalence of spotted fever in civil settlements in the 
neighborhood of his post."^^ When the surgeon general of the army 
requested particulars. Wood compiled reports from prominent Idaho 
physicians because, although he suffered a bout of the disease later, 
he had not at that time seen any cases. Their comments on spotted 
fever, published in the surgeon general's annual report, revealed well- 



A Blight on the Bitter root 



19 



honed powers of clinical observation but also reflected the endurance 
of the older miasma theory of disease causation, especially when spec- 
ulative bacteriological explanations did not correlate with epidemio- 
logical findings. 

C. L. Sweet, president of the Idaho State Medical Society, clearly 
described the rash, the "breakbone pains," and the low fatality of 
Idaho spotted fever. He advised symptomatic treatment for the pain 
and fever, noting that for mild cases he primarily prescribed placebos. 
Acknowledging that there were "indications which seem to point out 
this pecuhar affection as a water-borne disease," Sweet nevertheless 
was uncomfortable with this theory. "Frequently several cases occur 
in a household," he noted, while at other times "only the single case." 
This epidemiological picture militated against infection from a com- 
mon water supply. Instead, Sweet leaned toward "other circumstances" 
that favored spotted fever's similarity to malaria, a disease whose 
transmission by mosquitoes had not in 1896 been demonstrated. Spot- 
ted fever was frequently seen. Sweet noted, "in persons who have been 
living in the vicinity of newly broken ground, post holes, plowed 
ground, and in those who have drunk seepage water from worked 
soil, etc." In a similar analysis, L. C. Bowers speculated that the true 
cause of the disease "was probably of a telluric character," that is, 
arising from the earth itself.^^ Ticks or tick bites were never mentioned 
as possible factors. 

In October 1899, Edward E. Maxey, secretary of the Idaho State 
Medical Society, read a paper about spotted fever before the Oregon 
State Medical Society. Published in the Portland, Oregon, Medical 
Sentinel^ a journal that had been adopted by many western state med- 
ical associations as an official organ, Maxey's paper was the first on 
the disease in a medical periodical. Maxey observed that spotted fever 
was "in all probability, caused by some peculiar organism, possibly a 
miasm," but that "no specific cause" had "yet been discovered." He 
pointed out that the disease invariably occurred during the spring 
months and was primarily contracted "while residing, or sojourning, 
in or near the foot-hills of the mountains." Aware of the discoveries 
about contaminated water and infectious diseases, Maxey noted that 
while in the foothills of the mountains, victims had no other water 
supply than that which came from the melting snow. "In other words," 
he said, "they drank the snow water and became sick, therefore there 
must be, in my opinion, some specific cause for this disease, either in 
the soil over which the water runs, or in the snow itself. "^^ 

Maxey also differentiated between spotted fever and other diseases 
with which it had previously been identified. "After once seeing and 



20 



Rocky Mountain Spotted Fever 



recognizing spotted fever, the diagnosis is easy. . . . Even the laity 
recognize it on sight." Noting, however, that physicians had variously 
called it " 'dengue fever,' cerebro-spinal meningitis, typhoid, rheumatic 
purpura, typhus and measles," Maxey pointed out the seasonal, ge- 
ographic, or symptomatic differences between each of these diseases 
and spotted fever. He reiterated the optimistic prognosis for the disease 
as know^n in Idaho, and he did not mention the virulent form of spotted 
fever knov^n in the Bitterroot Valley. 

Although there were no published reports on this disease from other 
states at this time, in retrospect it is clear that spotted fever had been 
recognized during the last quarter of the nineteenth century throughout 
the northwest states. In Colorado a later survey noted that the disease, 
which exacted about a 23 percent mortality, had been known since 
1 8 8 5 . In Oregon spotted fever was reported to be well known to early 
physicians, "considered by them a mysterious disease with considerable 
mortality." Later statistics showed that the death rate in Oregon was 
"much less than in Montana" yet "somewhat higher than in Idaho." 
Spotted fever was reported most frequently in the central part of eastern 
Oregon, and, as was the case in Idaho and Montana, it seemed to be 
contracted in or near the foothills of the mountains. No case was 
known west of the Cascade Mountains."^^ 

In Wyoming spotted fever apparently had been known by the names 
mountain typhus, mountain sickness, mountain fever, and similar 
terms. The Indians of Wyoming reputedly knew of the disease but did 
not associate it with any particular region of the state. One old-time 
prospector who had crossed the plains into Wyoming during the days 
of the "bull trains" later told a Wyoming state health officer that 
spotted fever was commonly called trail typhus by emigrants traveling 
the Oregon Trail. It had plagued them particularly, he stated, from 
"the point where the trail joined the Sweetwater River about at In- 
dependence Rock" until they crossed the Green River. This description 
coincided with the central and north-central location of the majority 
of Wyoming cases. Like the situation in Oregon, moreover, mortality 
in Wyoming seemed to be about 15—20 percent— higher than in Idaho 
but lower than in the Bitterroot Valley. 

Other studies also concluded that spotted fever had been present 
from an early period in Washington, Nevada, Utah, and CaUfornia.'^^ 
Because the mortality in these states was relatively low, however, state 
authorities had not initiated investigations. The Montana State Board 
of Health, on the other hand, was confronted with the virulent spotted 
fever problem at the first meeting it held after being organized. The 
issue was raised by the Montana labor commissioner, Judson A. Per- 



A Blight on the Bitterroot 



21 



guson, who had been pressed to take action on the problem by Bit- 
terroot lumbermen, among whose ranks many victims of the disease 
were numbered. Ferguson had accordingly sent a questionnaire to 
Missoula and Bitterroot Valley physicians asking for as much infor- 
mation as possible about spotted fever. He presented the replies at the 
meeting of the state board on 9 May 1901.^"^ 

Although the board was principally concerned at this meeting with 
a smallpox epidemic in the state and with establishing rules for licensing 
undertakers, the members listened to Ferguson's report and expressed 
willingness "to call a special meeting at any time to consider the matter" 
of spotted fever. Desiring more scientific information, the board au- 
thorized Emil Starz, who was appointed state bacteriologist later that 
summer, to make a bacteriological investigation of the disease. Ac- 
companied by Ferguson, Starz visited the valley, took water and soil 
specimens, and obtained "cultures" from one spotted fever patient, 
which he inoculated with negative results into two rabbits. On the 
basis of his research, Starz hypothesized that the disease was really 
"cerebrospinal meningitis combined with one or the other of pneu- 
monia or typhoid fever," but he also called for further investigation.^^ 

Physicians and laymen who had more direct experience with spotted 
fever disagreed sharply with Starz. "While he may be able to peep 
through a microscope and see things," wrote one Missoula doctor, 
"he doesn't know what he is talking about in this instance."^" Although 
no one else had any additional scientific evidence to offer about the 
disease, many theories were advanced. Melted snow water as the source 
of the disease was the most popular theory with Missoula physicians, 
but one Bitterroot Valley doctor asserted that spotted fever was gen- 
erated by miasmas arising from north winds, which blew over decaying 
spring vegetation in swampland on the west side of the valley."*^ A 
layman from the Woodside area of the valley scoffed at this thesis. 
Edward Burrows noted that he had lived for twelve to fourteen years 
in the swampy area on the west side when it was virtually covered 
with timber, yet no spotted fever had then been known. "The land 
was cleared in the last six to seven years," he said, "and spotted fever 
began." Burrows did not suggest that the extensive lumbering oper- 
ations in the valley might be the cause of the disease but believed 
instead that miasmas from "dooryard filth" were the cause. 

There were more than a dozen cases of spotted fever during the 
spring of 1901— one official count noted fourteen cases with ten 
deaths. When compared with the number of deaths in Montana from 
smallpox, diphtheria, and typhoid, virulent spotted fever was not a 
widespread menace to pubUc health. Like the infrequent visitations of 



22 



Rocky Mountain Spotted Fever 



cholera and yellow fever, however, the few spring cases of spotted 
fever each year struck fear in valley inhabitants. The dramatic symp- 
toms of the disease— the blue-black rash, high fever, and delirium — 
and the high mortahty rate, especially among the healthy young adults 
who were among its most frequent victims, produced anxiety about 
an early and horrible death. Furthermore, this dread disease seemed 
a particularly cruel blight on the future development of one of the 
most beautiful valleys in the western United States. Proposals for at- 
tracting new residents who wished to grow apples on irrigated farms 
were already being discussed, and the west side of the valley was prime 
land for this purpose. If a deadly infection lurked in the west side 
canyons, however, prospective land buyers would be understandably 
reluctant to place themselves in jeopardy. Economic aspirations of 
valley residents thus fueled a desire to "do something" about spotted 
fever. Decisions made by the Montana State Board of Health in the 
spring of 1902 addressed this demand and, in so doing, launched 
twentieth-century research efforts to understand, prevent, and treat 
this mysterious disease. 



Chapter Three 



The Beginning of Scientific 
Investigations 

The great tragedy of Science— the staying of a beautiful hypothesis by an 
ugly fact. 

Thomas Huxley, Collected Essays 



In 1902 scientific experts began a decades-long search to elucidate 
the etiolog)', prevention, and treatment of the mysterious spotted fever 
of the Rocky Mountains. During the first nvo seasons of this work, 
in 1902 and 1903, it seemed that the etiolog)^ of spotted fever might 
quickly be explained, for the evidence indicated that the disease was 
caused by a protozoan organism transmitted by the Rocky Mountain 
wood tick. In 1904, however, this theory was called into question by 
other scientific specialists. For the inhabitants of the Bitterroot con- 
tinually at risk of contracting the disease, each new finding seemed 
only to make it clear that their strange disease was more complex than 
anyone had previously envisioned. 

Placing spotted fever investigations on a scientific basis began at the 
February 1902 meeting of the Montana State Board of Health. Since 
cases of the malady rarely appeared before mid March, the board 
could do little at the time, but it agreed unanimously to pursue the 
problem "as soon as the occasion arose." In early April spotted fever 
struck near Florence, a well-known infected area. By the end of the 
month there had been five cases in the valley, three of which were 
from the Hamilton area, south of the Florence — Lo Lo spotted fever 
district, and concern was voiced that the disease was spreading.^ 

The RavalH Count)' Board of Health met on 28 April to discuss the 
problem. Local physicians affirmed that this disease was neither typhus 
nor cerebrospinal meningitis, the two "spotted fevers" discussed in 
medical textbooks. They called for the state board of health to employ 
an expert pathologist to study the problem scientifically.^ The Montana 
state labor commissioner, Judson A. Ferguson, who had initially 



^3 



2-4 



Rocky Mountain Spotted Fever 



brought the spotted fever question to the attention of the state board 
in 1 90 1, also pressed the board for "decisive measures" to suppress 
the disease that attacked many of the lumbermen who were his con- 
stituents.^ 

Responding to this outcry, members of the state board of health 
visited the valley in early May. The board's secretary, Albert F. Longe- 
way, brought along Earle Strain, a medical colleague from Great Falls 
who had studied bacteriology in Europe. When Strain noticed a tick 
in the hair around the genitals of a spotted fever victim, he reportedly 
recalled a lecture given by John Guiteras at the University of Penn- 
sylvania on mosquitoes as the vector of yellow fever. He suggested to 
Longeway that the tick might have a similar connection with spotted 
fever.^ 

On the whole, however, Longeway was disappointed that little was 
accompUshed by this visit "aside from obtaining information about 
past illnesses and specimens of water and soil for laboratory study," 
but he decided that the services of a scientific expert were indeed 
needed. He wired Governor Joseph K. Toole, who was in Washington, 
D.C., attending a family funeral, for permission to act. Toole's reply 
instructed Longeway "to employ the best skill that money could secure 
and carry to conclusion a most thorough investigation."^ 

Armed with the governor's approval, Longeway consulted H. M. 
Bracken, secretary of the Minnesota State Board of Health, who, along 
with Frank F. Wesbrook, director of that board's bacteriological lab- 
oratory, suggested two young pathologists on their staff as potential 
investigators. The two, whose services Longeway promptly engaged, 
were Louis B. Wilson, an assistant bacteriologist with the state board 
and senior demonstrator in pathology at the University of Minnesota, 
and WiUiam M. Chowning, a junior demonstrator in pathology at the 
university and staff pathologist to Saint Mary's Hospital and the Min- 
neapolis City Hospital. Born in 1866, Wilson had studied with Wes- 
brook as a medical student at the University of Minnesota, after which 
he spent a period at Harvard with Frank Burr Mallory, who developed 
many of the tissue stains widely used in histologic pathology.^ Wilson's 
resulting laboratory expertise earned him second author status in 1900 
on a distinguished Wesbrook paper concerning the varieties of the 
diphtheria bacillus.^ Wilson's associate, twenty-nine-year-old William 
M. Chowning, had taken undergraduate degrees at Knox College and 
Johns Hopkins University and had just completed his M.D. in 1901 
at the University of Minnesota Medical School.^ The Montana State 
Board of Health hoped that Wilson and Chowning, with their expertise 



The Beginning of Scientific Investigations 



2-5 




In 1902, Louis B. Wilson (left) and William M. Chowning, young patholo- 
gists from the University of Minnesota, launched scientific investigations 
into Rocky Mountain spotted fever. Wilson later pursued a distinguished 
career at the Mayo Clinic in Rochester, Minnesota. Chowning returned to 
the private practice of medicine. (Courtesy of the Rocky Mountain Labora- 
tories, NIAID.) 

in pathology and bacteriology, would be able to shed light on the 
Bitterroot's strange blight. 

Because the spotted fever season v^as so short each year, the two 
pathologists began v^ork almost immediately. Arriving in Missoula on 
16 May, Wilson wa.s joined by Chowning on 26 May. With apparatus 
and media brought from Minnesota, they established a laboratory in 
a Northern Pacific Hospital room made available for the work. The 
railroad company was eager to assist in the spotted fever investigations, 
because the expansion of its rail lines into Idaho was jeopardized by 
the disease, as was its supply of lumber for ties from the Bitterroot. 
The physicians who administered the hospital, J. J. Buckley and E. W. 
Spottswood, cooperated fully with the visiting investigators, loaning 
the two men additional equipment. The arrival of Wilson and Chown- 
ing marked the beginning of scientific research into Rocky Mountain 
spotted fever.^ 



26 



Rocky Mountain Spotted Fever 



The investigation was broad: data were gathered from epidemio- 
logical, clinical, pathological, and laboratory studies. Within the first 
ten days, the two pathologists conducted three autopsies; subsequently 
they conducted five more. Victims of spotted fever, they observed, 
showed an enlarged spleen and small hemorrhages in the kidneys and 
at the base of the left ventricle of the heart. Most other organ systems 
appeared normal. Employing staining techniques by which the minute 
changes in tissues could be seen under the microscope, Wilson and 
Chowning found that the capillaries of the skin were distended and 
that many blood cells had escaped into the surrounding tissue. This, 
of course, explained the presence of the "spots. 

To gather epidemiological evidence, Wilson wrote each physician 
in the Bitterroot and Missoula, asking for detailed case histories on 
spotted fever patients. He enclosed a blueprint map of the valley on 
which the suspected point at which victims contracted the disease was 
to be marked with "a pen dipped in a strong solution of common 
baking soda." The response was satisfying— all but one physician re- 
sponded, providing information from their records on 114 cases. 

Data from the blueprint maps were combined on a master map that 
showed definitively the sharp localization of spotted fever on the west- 
ern side of the Bitterroot Valley. Two other foci were also identified 
outside the valley in western Montana. In the Bitterroot, furthermore, 
the infected district did not include the entire west side of the valley. 
A later observer noted: 

The boundary of the endemic area is not formed by the river but by the margin 
of the "bench" or foothills. People living in the river bottom, even on the west 
side, feel secure. . . . Exposure or residence on the "bench" might for some 
reason be more dangerous than in other near places because of the difference 
in the development. The east side of the valley is cleared thoroughly, highly 
cultivated, v^ell settled and in thrift and prosperity resembles a fat Pennsylvania 
or Ohio Valley. The west side, especially the "bench," is not nearly so advanced. 
Much of it is not cleared at all, very little is well cultivated. The houses as a 
rule, are poor and there is a difference of many years in the advancement of 
the two sides. 

Other information from Wilson and Chowning's epidemiological 
study revealed that the earliest recorded case began on 17 March and 
the latest about 20 July, with most cases occurring between 15 May 
and 15 June. An analysis of the sex and age of victims revealed that 
although the disease had occurred in both sexes and in all age groups, 
the highest incidence was in males between 20 and 40 years old— a 
total of 41 cases in this group — and in females between 10 and 20 
years old or between 30 and 40— there were 11 cases in each of these 




Highlighted version of the epidemiological map prepared in 1902 by Louis B. 
Wilson and William M. Chowning during their study of spotted fever in the Bit- 
terroot Valley. The horizontal line near the top marks the political division be- 
tween Missoula and Ravalli counties. The dots representing cases clearly shov^ 
the concentration of the disease on the benchlands and in the canyons west of the 
Bitterroot River. (From Louis B. Wilson and William M. Chov^ning, "Studies in 
Pyroplasmosis Hominis: ['Spotted Fever' or 'Tick Fever' of the Rocky Moun- 
tains]," /owr«<3/ of Infectious Diseases i [1904]: 31-57.) 



28 



Rocky Mountain Spotted Fever 



TABLE I. 


Wilson and Chowning's Record 


of Spotted Fever Cases 




by Age and Sex 


of Patients 










Males 






Females 


Total 


Age 


Cases 


Deaths 


Cases 


Deaths 


Cases 


Under 5 


8 


4 


5 


5 


13 


5-10 


6 


5 


7 


4 


13 


10-20 


8 


5 


11 


5 


19 


20-30 


17 


13 


7 


3 


24 


30^0 


OA 


1 Q 


1 1 


7 


J J 


40-50 


8 


6 


2 


1 


10 


50-60 


3 


2 


2 


1 


5 


60-80 


4 


4 


2 


2 


6 


Not stated 


1 


1 


0 


0 


1 


TOTAL 


79 


59 


47 


28 


126 



SOURCE: This table is adapted from Louis B. Wilson and William M. Chowning, "Studies in 
Pyroplasmosis Hominis" ('Spotted Fever' or 'Tick Fever' of the Rocky Mountains)," Journal of 
Infectious Diseases 1 (1904): 36. It includes information on cases studied in 1903 in addition to 
the 114 cases on which records were compiled in 1902. 



two age groups (see Table i). Wilson and Chowning attributed the 
higher infection rate in these groups to the "increased exposure to 
infection through their occupation or pleasure taking them outdoors 
in the foothills and mountains in the spring of the year." From clinical 
histories of the cases, moreover, Wilson and Chowning noted that the 
"general health of the patient" had "little part in determining suscep- 
tibility to the disease." In general, victims of spotted fever were healthy 
before the disease struck them down.^"^ 

Wilson and Chowning determined that between 1895 ^^'^ 1902, 
the years during which spotted fever had become a fearsome presence 
in the valley, there had been 88 cases with 64 deaths, producing an 
average mortality of 72.7 percent. Their records correlated closely 
with newspaper reports during these same years, the newspapers re- 
cording 92 probable cases with 64 deaths, a mortality rate of 69.56 
percent (see Table 2).^^ As a part of their examination of the "to- 
pography, meteorology and water and food supply," moreover, they 
found that "in no instance have two or more persons with the same 
food or water supply been simultaneously stricken with the disease." 
This finding cast doubt on melted snow water as the source of the 
infection. Neither was spotted fever contagious. "There is not even a 
suspicion," they wrote, that the disease had ever been "transferred 
directly from one human being to another, except in one instance, in 



The Beginning of Scientific Investigations 



29 



TABLE 2. Cases and Deaths from Rocky Mountain Spotted Fever, 



Year 


Wilson and Chowning 




Newspapers 


Cases 


Deaths 


Cases 


Deaths 


1895 


3 


3 


6 


6 


1896 


6 


6 


9 


7 


1987 


6 


5 


12 


9 


1898 


3 


2 


11 


8 


1899 


23 


14 


10 


3 


1900 


12 


9 


14 


11 


1901 


14 


10 


17 


10 


1902 


21 


15 


13 


10 


TOTAL 88 


64 


92 


64 




Average mortality 


72.73% 




69.57% 



SOURCE: Louis B. Wilson and William M. Chowning, Report, Montana State Board of Health, 
First Biennial Report, 1901-1902, 32-41; idem, "Studies in Pyroplasmosis Hominis," 33; local 
newspapers as cited in Robert N. Philip, "A Journalistic View of Western Montana, 1870-1910: 
Some Newspaper Items Relevant to the Development of the Bitter Root Valley and the Occurrence 
of Rocky Mountain Spotted Fever," manuscript, 1984, passim. 



which an infant born while the mother was suffering from the disease" 
also developed spotted fever. What they found instead— in every case 
they personally examined— were "small wounds of the skin, said to 
have been made by the bites of ticks." Working from this epidemio- 
logical picture, Wilson and Chowning began a series of laboratory 
experiments to elucidate the microscopic etiology of spotted fever. 

The intellectual milieu in which the two pathologists launched their 
laboratory studies was strongly influenced by recent discoveries relating 
to microorganisms and their potential vectors. Epidemiological data 
from earlier periods, for example, such as those gathered in the 1848- 
49 London cholera epidemic by John Snow, had suggested that con- 
taminated water might be one vector by which bacteria were trans- 
mitted. This theory was confirmed in 1884 when Robert Koch dis- 
covered the comma-shaped bacillus of cholera, and subsequently water 
was suspect whenever a new disease was investigated. That the lay 
population of the Bitterroot was familiar with the concept of water- 
borne disease is evident in the popularity of the theory that held melted 
snow water to be the source of spotted fever. 

Another recently discovered route by which bacterial diseases were 
spread was insects, such as flies and mosquitoes, and other arthropods 
such as ticks and mites. Transmission of bacterial diseases by insects 



30 



Rocky Mountain Spotted Fever 




The Rocky Mountain wood tick, male and female Dermacentor andersoni, 
the first tick identified as a vector of Rocky Mountain spotted fever. 
(Courtesy of the Rocky Mountain Laboratories, NIAID.) 



was believed to be a mechanical process: the insect accidentally picked 
up bacteria on its wrings, feet, or mouth parts and carried them to food 
or other items contacted by a human or animal host. The Spanish- 
American War of 1898 had produced a convincing and well-publicized 
indictment of one insect, the house fly, in connection with the me- 
chanical transmission of typhoid fever. An official investigation of the 
typhoid epidemic in U.S. camps documented the proximity of open 
latrines to cooking tents, noted the swarms of flies with access to both, 
and concluded that authorities concentrating on the purity of the water 
supplies had neglected to address the threat of transmission of typhoid 
by flies.i" 

A second line of inquiry about arthropods and disease had grown 
out of research in helminthology, the study of parasitic worms. In 
1878, Patrick Manson, a British medical officer studying the life cycle 
of Filaria bancrofti, the worm that causes the tropical disease filariasis, 
discovered that a portion of the worm's life cycle was spent in the 
body of a mosquito. Manson's research inspired Ronald Ross, an- 
other British medical officer, to complete experiments that in 1898 
demonstrated the presence of the malaria parasite, a protozoan rather 
than bacterial organism, in the mid guts of Anopheles mosquitoes. 
Although credit for this discovery was shared with Italian investigator 
Giovanni Battista Grassi and his collaborators, Ross reaped high hon- 
ors. Fellowship in the Royal Society, a Nobel prize, and knighthood 



The Beginning of Scientific Investigations 



31 



followed the realization that mosquito control measures might rid the 
world of the scourge of malaria and improve the habitability of Eu- 
rope's tropical colonies. ^° 

Five years before Ross's achievement, Theobald Smith and Fred 
Lucius Kilbourne, a physician and a veterinarian working in the Bureau 
of Animal Industry of the U.S. Department of Agriculture, published 
the results of their experiments on Texas cattle fever. They proved 
conclusively that this disease, which resulted in a significant economic 
loss to owners, was caused by the presence in the blood of a protozoan 
organism transmitted to the cattle by the bite of an infected tick. 
Moreover, they demonstrated that dipping cattle to kill ticks would 
effectively prevent the disease. 

The disease organisms of filariasis, malaria, and Texas cattle fever 
spent some portion of their life cycles developing in the body of an 
intermediate arthropod host, which passed them on to humans or 
animals through direct inoculation by biting. This developmental phe- 
nomenon, not shared by bacteria, defined initially the concept of bi- 
ological transmission of disease by arthropods. Pathogenic helminths 
and protozoa, moreover, could not be cultured as bacteria were. The 
discovery that microorganisms other than bacteria could be sources 
of disease offered an explanation for a major problem besetting bac- 
teriologists. Robert Koch had included as one of his postulates for 
demonstrating bacterial etiology of disease the isolation and culture 
on an artificial medium of the suspected organism. Attempts to cul- 
ture the organisms of yellow fever, rabies, and several other diseases 
had proven fruitless, but after the discoveries of Manson, Ross, and 
Smith and Kilbourne, many researchers suspected that the elusive or- 
ganisms of a number of dread diseases were pathogenic protozoa or 
helminths. When the U.S. Yellow Fever Commission in Cuba dem- 
onstrated that Yellow Jack was a mosquito-borne disease, this sus- 
picion became a working hypothesis. 

At the time these discoveries were made, moreover, the concept of 
the virus as a distinct pathologic entity did not exist. The term virus 
was used only in the general sense, like the word germ, to mean 
"infectious agent." As such, it was appHed to bacterial, protozoan, 
and unknown pathogens. A few physical scientists argued that the so- 
called filterable viruses might be nonliving substances, but most medical 
and bacteriological researchers, who were advocates of the germ the- 
ory, supported the idea that ultramicroscopic agents were tiny, living 
microbes. 

The intellectual concepts that emerged from these findings linked 
bacterial diseases to mechanical transmission of diseases by arthropod 



32 



Rocky Mountain Spotted Fever 



vectors and protozoan diseases to biological transmission. Most re- 
searchers never concluded that these relationships were rigid, but in 
the face of no conflicting evidence, they often came to assume them 
as truth. In 1899, for example, George H. F. Nuttall, founder of the 
journal Parasitology^ published the first exhaustive study of arthropod 
vectors. Simply by focusing on know^n information and adopting a 
skeptical attitude about alternative hypotheses, Nuttall reinforced such 
assumptions. In his section on ticks, he discounted the likelihood that 
they carried any sort of bacterial infection biologically, but he discussed 
at length tick transmission of protozoan diseases, especially Texas cattle 
fever.^^ 

This model of hov^ nature operated was powerful in suggesting what 
sort of disease to suspect given a known insect vector. House flies, for 
example, were known to carry bacterial diseases, but ticks and mos- 
quitoes should be suspected of carrying protozoan diseases. Con- 
versely, if a disease were of known bacterial origin, accidental trans- 
mission by an insect should be investigated, while if a protozoan or 
helminth had been identified, an arthropod that transmitted the disease 
biologically might be the likely culprit. During the first three decades 
of the twentieth century, the elegant logic of these concepts exerted a 
powerful influence on researchers in infectious diseases, including Wil- 
son and Chowning and subsequent investigators of Rocky Mountain 
spotted fever. 

All of the patients Wilson and Chowning examined had been bitten 
by wood ticks from two to eight days before the onset of the disease, 
hence they suspected the tick as the likely vector. Local citizens, more- 
over, may also have suggested the possibility of tick transmission, for 
ticks had occasionally been associated with "blood poisoning."^^ By 
analogy with known diseases transmitted by ticks, Wilson and Chown- 
ing doubtless theorized that a protozoan organism might be the in- 
fectious agent. To rule out possible bacterial causation, however, they 
examined fresh blood from patients and also attempted to culture 
bacteria from blood in a variety of media. All of these studies were 
negative, so they concluded that the disease was not caused by a 
bacterium. In the blood of eight patients, however, they believed that 
they saw "ovoidal bodies" that exhibited "amoeboid movements." 
Their studies convinced them that these bodies were a hitherto un- 
described "hematozoan," a protozoan parasite that lived all or a part 
of its life cycle in the circulating blood of its host.^^ They announced 
their findings to the local press June 7. 



The Beginning of Scientific Investigations 



33 



We find the disease to be a disease of the blood. It is due to a parasite which 
infests the red blood cells. This parasite . . . resembles the parasite which 
causes malaria. The parasite apparently does not gain access to the body by 
way of the nose or mouth; that is, it is not carried by the air, drinking water 
or food, but is injected into the blood by some biting insect or animal. . . . 
All the facts point to some kind of a tick as carrying the disease to man by 
its bite. All of the above facts are circumstantial though not positive evidence 
that the parasite of spotted fever is conveyed to man through the bite of some 
small slowly moving animal or insect which is found early in the spring and 
disappears about July and only a few individuals of which are infested with 
the parasite. The tick answers to this description, though much work may yet 
be needed to determine its exact relationship to conveyance of the disease.^* 

Wilson and Chowning identified the hematozoan organism as a 
Pyroplasma, other species of which were known to cause Texas cattle 
fever and similar blood diseases in horses and dogs. They proposed 
that the organism be named Pyroplasma hominis, or "the pyroplasma 
of humans." Shortly after they published their findings regarding this 
organism, it should be noted, their spelling was corrected to Firoplasma 
to conform with accepted zoological nomenclature. They described 
three stages in which they found the organism, which they said varied 
in size from one to three microns in thickness and from two to five 
microns in length. This piroplasma, they stated, resembled "in its 
smaller form very markedly the Pyrosoma bigeminum of Texas fever, 
yet [it] differs from that organism in being larger, and in its larger 
forms exhibiting active ameboid movements with the projection of 
pseudo-podia. The absence of pigment from the organism of 'spotted 
fever' would apparently separate it from the malarial group and place 
it with that of Texas fever."^° 

Although they admitted that this newly described organism was not 
always easy to find in blood, many protozoan organisms were similarly 
difficult to locate. What doubtless convinced them that the elusive 
organism was indeed the cause of spotted fever were the other elements 
in the paradigm under which they operated. The disease was most 
prevalent during the spring of the year, the time when ticks were 
plentiful. All of the cases of the disease they observed had shown 
evidence of tick bite before the symptoms appeared. The local ground 
squirrel, Citellus columbianus, moreover, existed in large numbers in 
the valley, and it was presumed that this mammal served as the natural 
reservoir of the disease, from which the infected ticks contracted it. It 
was known, moreover, and pointed out by a later observer, that the 
ground squirrel would not cross water except under extraordinary 
circumstances. "This being true, it would give the necessary expla- 



34 Rocky Mountain Spotted Fever 

nation why the disease was confined" to the western side of the valley 

Regarding the relationship between the parasite and the tick, Wilson 
and Chowning noted: "All hematozoa of warm-blooded animals, of 
which the life cycle is now known, pass at least one phase of their 
development within the body of some host (usually an insect or arach- 
nid) other than the one whose blood cells they invade. This is probably 
also true of the hematozoan of 'spotted fever.' " They also noted that 
in both malaria and Texas fever, only one species of mosquito or tick 
carried the organism and not all members of the species were infected. 
This comment was offered to explain the low incidence of infection 
in the Bitterroot, because, as the local people noted, it was impossible 
to escape being bitten during "tick season" each spring.^^ 

The P/ro/7/<3sm^2-tick-ground squirrel theory of spotted fever con- 
tained all the elements of an elegant solution to a scientific mystery, 
and it was, as a later writer noted, "in the Hne of some of the most 
fashionable thought" of the time.^^ It conformed to prevailing beliefs 
about the relationship between protozoan organisms and biological 
transmission of disease; it identified a common mammal as probable 
host in nature; and it squared with the epidemiological data on the 
disease. Furthermore, this theory also gained currency from immediate 
experience. On 14 June, a week after Wilson and Chowning had 
announced their findings, Dan McDonald, a lumberman who worked 
on the west side of the valley near Victor, discovered a tick attached 
to his body. As he took it off, he remarked, "Now we shall see whether 
this gives me the spotted fever or not." Fourteen days later he died of 
the disease. 

While Wilson and Chowning were conducting their research in the 
Bitterroot, Montana Congressman Caldwell Edwards had been dis- 
cussing the spotted fever situation with Walter Wyman, surgeon general 
of the U.S. Public Health and Marine Hospital Service. In 1901 this 
Service, founded to serve the medical needs of merchant seamen, re- 
ceived congressional authorization to investigate "infectious and con- 
tagious diseases and matters pertaining to the public health." Edwards 
or others had indicated to Wyman that spotted fever was "highly 
communicable and, therefore, a matter of importance to the pubhc 
health of the country." The presumed contagious nature of the disease 
placed it within the Service's purview, hence on 23 June, Wyman 
telegraphed one of his commissioned officers, Surgeon Julius O. Cobb, 
to proceed to Montana to investigate the disease. 

The thirty-nine-year old Cobb, a fourteen-year veteran of the Service 
from South Carolina, had considerable experience investigating out- 
breaks of disease. Having contracted yellow fever in 1897, moreover, 



The Beginning of Scientific Investigations 



35 



he doubtless had a keen appreciation of the new information regarding 
the biological transmission of disease by arthropods. Cobb reviewed 
the findings of Wilson and Chowning and agreed with their conclu- 
sions. In his report to Surgeon General Wyman, Cobb stated that he 
omitted "many interesting facts" because they had been published 
already by Wilson and Chowning as a preliminary note in the Journal 
of the American Medical Association. He summarized the findings of 
the two Minnesota pathologists and, from his own investigation, was 
satisfied that they had indeed found a hematozoon in the blood of 
spotted fever victims that was probably transmitted to humans by the 
wood tick from a natural reservoir in the local ground squirrel. Assured 
that the investigations were on the right track, Cobb noted that the 
original fear of contagion was "altogether groundless," and com- 
mented that "the alarm caused by newspaper reports" was "unjusti- 
fiable."^^ 

At the end of the 1902 spotted fever season, Wilson and Chowning 
submitted to the Montana State Board of Health a bill for $1,466, 
which, in light of the board's annual budget of $2,000, starkly revealed 
the high cost of scientific research. For this sum, the investigators had 
produced a logical but unproven theory regarding the cause of spotted 
fever. They had not, however, developed any method to prevent or to 
cure the malady. At the meeting of the state board during which the 
expenses were allowed, there was considerable discussion about the 
investigation of spotted fever and about the state's authority for un- 
dertaking it. The board concluded that no more state money would 
be spent on spotted fever in 1902, and that the county commissioners 
of Missoula and RavaUi counties, where the disease was localized, 
should endeavor to raise the funds needed for further research in 
1903.^^ 

Faced with the possibility of no further state support for their medical 
crisis, the commissioners of RavaUi County appropriated $400 in April 
1903 for continued investigations. They added a caveat, however, 
stipulating that Missoula County must raise a matching amount. The 
commissioners of Missoula County balked, according to newspaper 
accounts, because they beHeved that spotted fever was "more than a 
two county problem." It was also widely believed that the Montana 
congressional delegation could persuade the U.S. Public Health and 
Marine Hospital Service to fund and conduct the investigation.^^ 

With its sparse population, Montana was allocated only one seat 
in the U.S. House of Representatives and, of course, two Senate seats. 
This three-man delegation, comprised of Congressman Joseph M. 
Dixon, who later became governor of the state, and Senators William 



36 



Rocky Mountain Spotted Fever 



A. Clark and Paris Gibson, actively pressed the case and did indeed 
persuade Surgeon General Walter Wyman to continue federally spon- 
sored research into spotted fever. The Service officer Wyman chose to 
study spotted fever in 1903 w^as Passed Assistant Surgeon John F. 
Anderson, w^ho had demonstrated such competence in research that 
in 1902, at age twenty-nine, he had been named assistant director of 
the Service's Hygienic Laboratory. A Virginian, Anderson, after com- 
pleting medical school, had done graduate v^ork in bacteriology in 
Europe, including a period at the School of Tropical Medicine in 
Liverpool, where he studied protozoan organisms similar to the pre- 
sumed agent of spotted fever.^^ 

Anderson left Washington on 24 April, stopping in Great Falls, 
Montana, to confer with the secretary of the Montana State Board of 
Health, A. F. Longeway; then he continued on to Missoula, where he 
was offered the use of laboratories at the University of Montana and 
at the Northern Pacific Hospital. He decided to make his headquarters 
at the Northern Pacific in order to work closely with Wilson and 
Chowning, who had returned for an additional month's work in 1903. 
The Minnesota researchers shared their data with Anderson and stud- 
ied five new cases of spotted fever, performing one autopsy. Anderson, 
whom they taught to stain the sHdes of blood in order to see the 
organism they had described, believed he saw two of the three forms 
Wilson and Chowning had described. "I was unable to find the paired 
form in stained preparations," he later wrote, "though Drs. Wilson 
and Chowning informed me that they had no difficulty in doing so." 
Anderson also collected specimens of the ticks suspected of being 
infected with spotted fever and sent them to the Hygienic Laboratory 
for identification by Charles Wardell Stiles, director of the laboratory's 
Division of Zoology. 

Like Cobb before him, Anderson was convinced that Wilson and 
Chowning had identified the spotted fever organism and that their 
theory of tick transmission was correct. Upon returning to Washington, 
Anderson published a lengthy report on spotted fever in a Bulletin of 
the Hygienic Laboratory. It recapitulated Wilson and Chowning's work 
and included their case histories and maps."^^ Anderson also inserted 
photographs and drawings of the eruption of the disease, which he 
proposed be called tick fever instead of spotted fever because the latter 
name was frequently identified with typhus and cerebrospinal men- 
ingitis. The only point on which Anderson disagreed with Wilson and 
Chowning had to do with the ground squirrel as the probable host in 
nature. Knowing that the Piroplasma of Texas cattle fever would not 



The Beginning of Scientific Investigations 



37 



infect sheep nor would the Piroplasma of dogs infect cats, Anderson 
doubted that a Piroplasma of ground squirrels would easily infect 
humans. Because of his skepticism about this hypothesis, Anderson 
omitted any mention of the ground squirrel from his report."^^ 

Satisfied that their 1903 investigation had confirmed the work of 
1902, however, Wilson and Chowning also collaborated on a detailed 
scientific article, pubHshed in 1904 in the premiere issue of the Journal 
of Infectious Diseases. Entitled "Studies in Pyroplasmosis Hominis 
('Spotted Fever' or 'Tick Fever' of the Rocky Mountains)," the paper 
included drawings of the presumed protozoan organism of spotted 
fever as well as epidemiological, pathological, microscopic, and clinical 
evidence supporting the tick transmission theory. 

Most inhabitants of the Bitterroot Valley accepted the scientific ex- 
perts' verdict that the tick was the culprit in transmitting spotted fever. 
Because ticks were so pervasive during the spring, however, implicating 
them as vectors of a dread disease had immediate economic conse- 
quences, especially for property owners and sawmill operators on the 
west side of the valley where the infection was locafized. One observer 
noted: 

Economically, I think it safe to say that the tick theory has been more disastrous 
to the infected region than the disease itself. Ticks are so common it is nearly 
impossible for a man working out of doors to avoid their bites, while at the 
same time they, if causing the disease, constitute a cause so tangible and real 
that the dissemination of this hypothesis excited a fear closely akin to terror. 
Land values were affected, probably a majority of the people on the west bank 
of the Bitter Root River desiring to sell and nobody willing to buy. Saw mills 
have been unable to procure a sufficiency of hands, and some families have 
sacrificed their property in order to get away as soon as possible. People who 
formerly frequented that region for business or pleasure could in most instances 
not now be induced to go there, except on most urgent business, during the 
tick season. 

As the implications of this natural calamity became manifest, civic 
leaders attempted to ameliorate the situation with pragmatic action. 
Taking stock of what was known about the disease, its tick vector, 
and the ground squirrel —or gopher as it was commonly known — 
which presumably served as a natural reservoir, they suggested that 
strong measures be taken to rid the valley of these threats. "It having 
been demonstrated that the woodtick is the cause of the so-called 
'spotted fever,' " an editorial in the Western News counseled, 

it would seem that the best preventive of the disease would be to put the 
venomous insect out of business. . . . The woodtick frequents localities only 



38 



Rocky Mountain Spotted Fever 



where there is much fallen and decayed timber. The abandoned settings of 
long-forgotten saw mills are its favorite haunts. These tick-infested localities 
should be scourged with flames. ... If the gopher is an ally of the woodtick, 
aiding and abetting it in its death dealing mission, it too must be exterminated."*"* 

By the following spring, preventive tactics w^ere widespread. The 
Western News reported in April 1904 that "farmers in the vicinity of 
Stevensville and points throughout the valley are making a strong effort 
this year to rid the country of the gopher pest. A new preparation of 
poisoned wheat is being generally used," the article continued, "and 
farmers all through the valley have laid in a big supply. The big increase 
in the number of these destructive spermophiles has alarmed the ranch- 
ers to no Httle extent." Some farmers believed, so the reporter noted, 
that the state should offer a bounty of five cents "for the scalp of every 
one of the animals exterminated.""^^ There was, however, one unfor- 
tunate side effect of the indiscriminate use of poisoned grain. Farmers 
who scattered it on the ground, hoping that the ground squirrels would 
eat it, often found that it killed game birds instead. 

Another approach to tick and gopher control was the burning of 
brush land. Reportedly done on the recommendation of John F. An- 
derson, a policy of spring burning was supported by the Forest Reserve 
office. "The great brooding [sic] places of the wood tick and gophers 
is in the old slash and cuttings along the foothills," reported the su- 
pervisor of the Bitterroot Forest Reserve, commenting also that "more 
spring burning this year has been done than during any three previous 
seasons. ""^^ 

Although these efforts may have heartened valley residents by pro- 
viding a means to strike back against a deadly enemy, it was impossible 
to exterminate all wood ticks. Careful and frequent examinations of 
the body to locate any ticks that had attached themselves thus became 
a ritual for many people. The Western News cautioned: "Should you 
be bitten by a woodtick, treat it as you would a snake bite. Be prompt 
in applying remedies to counteract the poison. Don't wait until the 
poison has permeated the entire system or you are likely to remain 
dead a long time.""^^ 

In response to this warning, many people, especially those who 
worked on the infected west side of the river, carried small bottles of 
carbolic acid for immediate application if a tick was found attached 
to them. Joseph Lister had popularized this chemical in the late nine- 
teenth century by using it successfully to kill germs in the operating 
room. Since Bitterroot citizens applied the mouth of the bottles to their 
skin directly over the tick bite, however, many suffered "small round 
sores from undiluted acid." The Ravalli Republican even reported that 



The Beginning of Scientific Investigations 



39 



on one occasion the cork had come out of a bottle in a man's pocket, 
"and the hot stuff burned him severely !"^^ 

Every theory regarding the cause of spotted fever, moreover, w^as 
carefully follow^ed and exploited by charlatans hoping to profit from 
the fear generated by the disease. During the heyday of the melted 
snow^ water theory, for instance, a number of people claiming to be 
scientists made a comfortable living testing drinking v^^ater for spotted 
fever infection. Within two weeks of Wilson and Chowning's an- 
nouncement that a hematozoon had been found in the blood of victims, 
the promoters of King's sarsaparilla capitalized on the new scientific 
evidence to advertise their product as a treatment. "Spotted fever has 
been pronounced a blood disease," the advertisement asserted. "Use 
King's sarsaparilla and you are exempt not only from spotted fever, 
but a great many other diseases. Two years later, a homeopathic 
physician in Missoula known only as Dr. Glasgow claimed that he 
had cured a sixteen-year-old boy of spotted fever within a few days 
by administering oral doses of "venom from a dagger-headed viper 
found in Brazil." Capitalizing on this post hoc, ergo propter hoc ar- 
gument, Glasgow advertised in the Daily Missoulian that his unusual 
therapy was good not only for spotted fever but also in cases of 
"arthritis and spinal conditions." In this period of unrestrained en- 
terprise, such exploitation was rampant. Not until 1906, with the 
enactment of the federal Pure Food and Drugs Act, were the worst 
abuses curbed. 

Quack treatments for spotted fever flourished, of course, because 
the orthodox medical profession could do Httle to treat the disease. 
After his investigation of spotted fever, for example, John F. Anderson 
suggested that physicians employ quinine therapy, "in large doses, 
preferably hypodermically," because of spotted fever's presumed sim- 
ilarity to malaria. Except for this strategy, which soon proved to have 
no beneficial effect and perhaps actually harmed patients, Anderson 
could only describe supportive therapies: strychnine, whisky, or other 
appropriate "cardiac stimulants" to support the heart; Dover's pow- 
ders or morphine sulfate to relieve the severe headache; large quantities 
of water to flush out the kidneys; and warm sponge baths to reduce 
the fever and refresh the patient.^^ 

At the conclusion of the 1903 tick season, it seemed even more 
probable than in 1902 that the wood tick was indeed the vector of 
spotted fever, but for all the monies and time expended, no effective 
cure or prevention had been found. The Montana State Board of Health 
was beleaguered by other pubHc health problems, especially nonco- 
operation from physicians who refused to report and enforce quar- 



40 



Rocky Mountain Spotted Fever 



antines for designated infectious diseases, such as measles. Secretary 
A. F. Longeway, moreover, seemed reluctant to enforce the board's 
rules vigorously/^ Possibly because of this, w^hen the board met on 5 
May 1903, Longew^ay v^as replaced as secretary by Thomas D. Tuttle/"^ 
The thirty-three-year-old Tuttle w^as a Missouri native v^ho had 
migrated to Montana after completing his medical studies in 1892 at 
the College of Physicians and Surgeons in New York/^ His initial 
activities and reports to the board revealed an energetic, no-nonsense 
approach to public health/^ Shortly after taking office, for example, 
Tuttle sought out Anderson and Chov^ning in Missoula to gather 
information on the spotted fever situation. 'T visited the bacteriologists 
investigating the 'Spotted Fever' in the Bitter Root Valley," Tuttle stated 
in his July quarterly report, "but was unable to learn that they had 
made any progress over the work accomplished last year." Realizing 
how little state money would be available to continue investigations, 
Tuttle wrote in early February 1904 to Senator Paris Gibson and 
Congressman Joseph M. Dixon of Montana for assistance in per- 
suading the U.S. Public Health and Marine Hospital Service to continue 
researching the disease. On 1 5 February he received a wire from Dixon 
stating that Anderson and another expert would be detailed to Mon- 
tana in March. When neither researcher had appeared by mid April, 
Tuttle again wrote Dixon, "asking him to hurry the matter along," 
since the spotted fever season had already begun and would end within 
three months. 

Surgeon General Walter Wyman responded by sending Montana his 
most experienced researcher in protozoan diseases, Charles Wardell 
Stiles, who had joined the Hygienic Laboratory in 1902 as the first 
director of the newly created Division of Zoology. Stiles had taken his 
Ph.D. in zoology in 1 890 with the distinguished Leipzig helminthologist 
Rudolph Leuckart and from 1891 to 1902 had served as principal 
zoologist for the Bureau of Animal Industry in the U.S. Department 
of Agriculture, where he worked alongside Theobald Smith and F. L. 
Kilbourne, discoverers of the Texas cattle fever piroplasma. Shortly 
before joining the U.S. Public Health and Marine Hospital Service, 
Stiles had won considerable fame by identifying a new species of 
hookworm and correctly deducing that it rather than malaria caused 
the anemia prevalent in the southern United States. For this work he 
had been hailed as the discoverer of the "Germ of Laziness. "^^ Surgeon 
General Wyman hoped that Stiles would be able to trace the hfe cycle 
of the parasite that caused spotted fever, study the tick that transmitted 
it and the ground squirrels that harbored the disease in nature, and 
arrive at a workable means of preventing the disease. 



The Beginning of Scientific Investigations 



41 




In 1904, Charles Wardell Stiles, director of the Division of Zoology at the 
Hygienic Laborator)^ of the U.S. PubUc Health and Marine Hospital Ser- 
vice, refuted Wilson and Chowning's assertion that a protozoan organism 
caused spotted fever. Because of widespread assumptions about microor- 
ganisms and their arthropod vectors, Stiles concluded that the disease was 
not transmitted by ticks. (Courtesy of the National Library of Medicine.) 



With his strong background in zoological subjects, Stiles was pre- 
disposed to look favorably on the findings of Anderson and Wilson 
and Chowning. In fact, Stiles looked upon the biological transmission 
of protozoa by arthropods as a law of nature rather than a working 
hypothesis. In April 1901, when he had presented the annual Toner 
Lecture, which he titled, "Insects as Disseminators of Disease," at 
Georgetown University, Stiles had stated: 

We may lay down two general biologic rules, which, I believe, are enunciated 
tonight for the first time: The first rule, to which at present a few exceptions 
are known, is that diseases which are accidentally spread by insects are caused 
by parasitic plants, particularly bacteria. The second, to which no exceptions 



42 



Rocky Mountain Spotted Fever 



are as yet known, is that those diseases which are dependent upon insects or 
other arthropods for their dissemination and transmission are caused by par- 
asitic animals, particularly by sporozoa and worms.^^ 

After working in the Bitterroot from 7 May to 6 July, however, 
during which time he saw ten patients, drew blood samples from nine, 
attended an autopsy on one, and conducted more than one hundred 
hours of work at the microscope. Stiles completely changed his mind 
about the earlier work.^^ He could find no trace of the reported or- 
ganism in the blood of spotted fever victims. In his microscopic work, 
Stiles was joined by U.S. Army physician Percy M. Ashburn, who was 
investigating the disease under orders from the surgeon general of the 
army. The two men worked independently but met almost daily to 
compare notes. "I used daylight, lamplight and electric light," Stiles 
wrote, "dry and oil lenses of Zeiss, Spencer, Leitz, and Bausch & 
Lomb. The specimens were taken at regular and irregular intervals, 
day and night, from both fatal and non-fatal cases." Stiles and Ashburn 
then consulted with Chowning, who was in the Bitterroot Valley at 
that time, but Chowning was unable to demonstrate the Piroplasma 
in the blood.^^ 

"Accordingly," wrote Stiles, "the work of 1904 has failed to confirm 
the conclusions of 1902 and 1903, and indications are not lacking 
that at least some of the stages of the supposed Piroplasma hominis 
consist in reality of vacuoles, blood platelets, blood dust, artifacts, and 
tertian malaria parasites. "^^ Later in the year, another U.S. Army phy- 
sician, Charles F. Craig, who had considerable experience investigating 
tropical diseases, reported in American Medicine the results of his own 
"most careful study of the subject." Confirming the findings of Ashburn 
and Stiles, Craig suggested that "Chowning, Wilson, and Anderson 
. . . have mistaken areas devoid of hemoglobin in the red cell ... for 
a protozoan parasite. "^"^ 

The evidence seemed overwhelming that no Piroplasma was present. 
Such organisms, however, were often difficult to find under the mi- 
croscope, so Stiles attempted to determine the presence of the organism 
by indirect means— by comparing symptoms of spotted fever with 
symptoms of known piroplasmic maladies, especially Texas cattle fe- 
ver. When he applied his wide knowledge of piroplasmic diseases in 
a comparison with spotted fever, however, he found few similarities. 
Most known piroplasmic diseases flourished in swampy valleys, but 
spotted fever occurred in the foothills of the Bitterroot Mountains. 
Piroplasmic diseases were also "apt to attack large numbers of patients 
at about the same time in the same locality," Stiles noted, and "if 
'spotted fever' is a piroplasmosis, transmitted by a tick, we should 



The Beginning of Scientific Investigations 



43 



expect a large number of cases to develop in any locality in which one 
case develops. This, hov^ever, is exactly what we do not find in 'spotted 
fever.' " This observation, he admitted, "was the first point to lead me 
to seriously doubt the tick hypothesis. "^^ 

Stiles continued, comparing one point after another about spotted 
fever and known piroplasmoses. No known protozoan disease was 
characterized by a rash, but in spotted fever the rash was the principal 
diagnostic sign. Victims of piroplasmosis normally became emaciated; 
victims of spotted fever appeared well nourished. In Texas fever the 
organism caused the blood to become "thin, watery, and pale," while 
the blood of spotted fever victims became "thick, molasses like, and 
dark." The bile in piroplasmosis became thickened, but in spotted 
fever the bile remained fluid.^^ Stiles concluded that the disease was 
not a piroplasmosis. The tick transmission theory and its corollary, 
the ground squirrel host, were totally dependent, in Stiles's thinking, 
on the presence of protozoan organisms. "An important point upon 
which I desire to place considerable stress," he stated, "is that the tick 
theory is a secondary hypothesis based upon the idea that 'spotted 
fever' is caused by a protozoon. If the Piroplasma theory is correct, 
the tick theory immediately receives a very strong argument in its 
favor, for other species of Piroplasma are known to have ticks as their 
intermediate host."^^ 

From his work in 1904, Stiles concluded that the earlier investigators 
had been wrong about the causative organism, about the tick trans- 
mission theory, and about the ground squirrel host. His own inves- 
tigation, however, yielded entirely negative results, for he produced 
"no new theories . . . regarding the cause, transmission, and origin of 
this disease. "^^ 

Although lacking evidence. Stiles offered some speculation about 
alternative causes that was, as he said, "in accord with the generally 
accepted view" regarding arthropods and disease. If spotted fever were 
not a protozoan disease, he reasoned, it must be a bacterial disease. 
If it were bacterial, it would probably be contagious. Supporting Stiles's 
contention, moreover, Percy M. Ashburn cited the cases of Mrs. Robert 
Allen, a twenty-eight-year-old housewife, and Miss Helen McConnon, 
a twenty-four-year-old schoolteacher, both of whom insisted that be- 
cause of heightened awareness that ticks might spread the disease, they 
had meticulously examined their bodies daily and had not been bitten 
by ticks before the onset of spotted fever.^^ Such evidence suggested 
to Stiles and Ashburn that contagion might be present. "It seems to 
me," Stiles wrote, "that the possibility is by no means excluded that, 
despite the general experience regarding the noncontagiousness of the 



44 



Rocky Mountain Spotted Fever 



disease, such close intimacy as sleeping in the same bed might perhaps 
result in a transmission of the disease to a healthy individual. 

Stiles also attempted to explain the seasonal occurrence of spotted 
fever within the existing theoretical framew^ork. "Practically all authors 
lay stress upon the fact that the affection under discussion is preem- 
inently a disease of the spring months," Stiles did not, however, relate 
the emergence of ticks to spring warming, but he did note the con- 
nection between the coming of spring and a rise in the amount of 
water in streams from melted snow. In fact, he revived the old theory 
that melted snow water might be a source of infection. "Such as the 
data are," he said, "they tend to support rather than to negative [sic] 
the popular idea that the melting snow has some direct or indirect 
connection with the development of cases, or . . . that conditions which 
favor the melting of the snow also favor the appearance of cases of 
spotted fever."^^ 

When he returned to Washington, Stiles published the most lengthy 
report on spotted fever yet produced. In addition to his scientific 
conclusions, he added an observation that would be used to question 
his integrity in later years. "The tick theory has caused serious financial 
loss to the Bitter Root Valley and has produced an effect which in a 
few cases had bordered on hysteria. In justice to the property interests 
of the valley and the peace of mind of the inhabitants, I think no time 
should be lost in publishing the statement that the results of study this 
year have absolutely and totally failed to confirm this hypothesis. "^^ 
This statement inspired one author to suggest that Stiles succumbed, 
at least unconsciously, to pressure from Bitterroot residents who re- 
jected the tick theory because of the damage it had already done to 
their property values. Such an interpretation misses the clear intel- 
lectual motivation behind Stiles's rejection of the tick hypothesis and 
ignores the responsibilities of government scientists in the Progressive 
era. 

Stiles, like other employees of government agencies, had to be re- 
sponsive to the concerns of his employers— the taxpayers of the United 
States. As James H. Cassedy has noted in his analysis of Stiles's hook- 
worm activities during this same period, such an awareness did not 
compromise a scientist's integrity, but it made him think twice before 
publishing findings that could have a potentially negative economic 
impact. Like most other government scientists during the Progressive 
era, Stiles was not doctrinaire on major political or social issues. For 
instance, in 1896 he strongly supported the extension of governmental 
authority to regulate filthy country slaughterhouses. He had also been 
willing, however, to apply his knowledge on behalf of U.S. pork prod- 



The Beginning of Scientific Investigations 



45 



ucers in 1898, when German restrictions on pork allegedly contami- 
nated with trichinosis threatened their livelihoods/"^ As a government- 
employed professional, Stiles could warn his colleagues that "diseases 
have an economic as well as an academic side," and caution them: "If 
it can be foreseen that a given working hypothesis is calculated to 
result in financial loss to an infected district, such hypothesis should 
be subjected to most searching criticism before it is published. And if 
it can be foreseen that any good to be accomplished by its announce- 
ment is far outweighed by its probable evil effects, its publication 
should be postponed until its correctness is demonstrated or is beyond 
reasonable doubt."^^ In a period when the status and authority of 
experts were increasing, it was the opinion of Stiles's zoological col- 
leagues that mattered to him, but when he found no evidence of tick 
transmission of spotted fever, he felt duty bound to correct the eco- 
nomic hardship produced by the "premature" conclusions about ticks 
and the disease published by Wilson and Chowning. 

The results of the work of Stiles, Ashburn, and Craig, coming at 
the end of two seasons of vigorous tick and gopher control efforts, 
left valley residents more mystified than ever about their strange dis- 
ease. The elegance of the Piroplasma-tick-gopher hypothesis had seem- 
ingly been destroyed by the "ugly little fact" that no Firoplasma existed. 
The intellectual model that Hnked only protozoan organisms to ar- 
thropod transmission, moreover, held such control over the thinking 
of the research community that no one seems to have considered the 
possibility that some other organism might be transmitted by the ticks. 
No one even attempted to verify tick transmission of the disease as a 
separate experiment.^^ Doubtless the scientific stature of Stiles, of army 
surgeon Ashburn, and of Craig, who had distinguished himself in 
tropical diseases during the Spanish-American War, added considerable 
authority to their conclusions about spotted fever. 

Although the spotted fever question was an intriguing intellectual 
problem for these men, they were not insensitive to the desire of valley 
residents for some means to combat the disease, which continued to 
claim victims each spring. In 1904 local newspapers reported fourteen 
cases of spotted fever and documented ten deaths. Among those who 
died was John Rankin, an early Missoula County pioneer whose daugh- 
ter Jeanette later served as a congresswoman from Montana. Percy 
M. Ashburn suggested a new approach to treatment, basing his notions 
on the presumption that a toxin-producing bacterium was possibly 
the cause of the disease. Employing an analogy with typhoid fever, 
Ashburn stated that "the grave symptoms" were probably produced 
by "a powerful toxin circulating in the blood; and the fact that we 



46 



Rocky Mountain Spotted Fever 



do not know the maker of the poison should not deter us from trying 
to ehminate it and to strengthen and sustain these parts and functions 
especially injured by it, until the organism has time to form the proper 
antibodies in sufficient amount to overcome the disease. "^^ 

What Ashburn suggested was the use of hydrotherapy, or water 
treatment, popularized by Simon Baruch and John Harvey Kellogg 
and recommended in 1892 as a treatment for typhus by the distin- 
guished Johns Hopkins physician, WiUiam Osler/^ Under the hydro- 
therapeutic regimen that Ashburn suggested, the patient was to be 
bathed in cold water at 70° F for ten to twenty minutes, while the 
attending nurse or physician constantly applied "hand friction to the 
body and limbs, with cold applications to the head." This procedure 
was to be repeated every three hours as long as the patient's temperature 
remained above 102.5° F. In difficult cases, ice water enemas, given 
while the patient drank alcohol or hot coffee — both considered stim- 
ulants—were said to increase the "efficiency of the bath and hasten 
the reaction." The theoretical basis of hydrotherapy rested on the 
observation that cold water and friction produced at first a contraction 
of the blood vessels followed by their dilation, which brought blood 
to the surface of the body where the heat of a fever might more readily 
be dispersed. "Quite possibly," Ashburn opined, "by so keeping up 
the tone of the peripheral vessels from the beginning of the disease 
they might be saved from the degeneration" that permitted hemmor- 
rhages into the skin and caused "the darkening of the spots." Re- 
portedly this cold water treatment was routinely employed in spotted 
fever cases by some Bitterroot physicians. ^° 

In the space of three years, the seasons of 1902, 1903, and 1904, 
scientific investigations of spotted fever had been launched, but the 
inconclusive results revealed only that the disease remained an enigma. 
Noting the muddled picture that emerged from the investigations of 
Wilson and Chowning, Anderson, Stiles, and Ashburn, an editorial in 
the Journal of the American Medical Association deplored the fact 
that the cause "of this strange disease is as obscure as ever," and called 
for a continuation of the investigation. "Further investigation is of 
great importance, not only from a scientific view but also from an 
economic point of view. The tick theory of the disease seems to have 
reduced the inhabitants almost to a state of panic, and it is hoped that 
the disease will be reinvestigated ... if only to reassure them and to 
render the development of this fertile valley practicable."^^ 



Chapter Four 



Dr. Ricketts's Discoveries 

Most of the knowledge and much of the genius of the research worker lie 
behind his selection of what is worth observing. It is a crucial choice, often 
determining the success or failure of months of work, often differentiating 
the brilliant discoverer from the plodder. 

Alan Gregg, The Furtherance of Medical Research 



By 1905 advances in many fields of science and technology were 
making tangible changes in American life. X-rays, for example, dis- 
covered just before the turn of the century, were already revolutionizing 
the practice of medicine. Similarly, if more gradually, the advent of 
electric Hghts, telephones, automobiles, phonographs, and vacuum 
cleaners was altering the daily lives of thousands of citizens.^ During 
this so-called Progressive era, optimism nourished by faith in the prom- 
ise of science also spurred reform movements to improve industrial 
slum conditions, to conserve natural resources, and to curb the abuses 
of unbridled capitalism. In the Bitterroot Valley of Montana, however, 
boosters hoping to attract new residents may have harbored doubts 
about the efficacy, or at least the efficiency, of science. The results of 
three years' work by highly regarded scientific experts had failed to 
uncover the cause of the valley's terrifying affliction, spotted fever. Yet 
the stalemate produced by conflicting theories was not a defeat but 
an indication that a new approach was needed. Beginning in 1906, 
valley residents would witness rapid progress in spotted fever inves- 
tigations as researchers, especially Howard Taylor Ricketts of the Uni- 
versity of Chicago, studied past findings and explored the question 
from new directions. 

In June 1904 the secretary of the Montana State Board of Health, 
Thomas D. Tuttle, attended the second annual meeting of state and 
territorial health officers with the surgeon general of the U.S. Public 
Health and Marine Hospital Service to lobby for continued investi- 
gations of spotted fever by the federal government. Noting enthusi- 
astically in his report to the board the "hundreds of little points" 



47 



48 



Rocky Mountain Spotted Fever 



regarding health work he obtained at the meeting, Tuttle related the 
considerable interest that Montana's "unknown" disease engendered 
in other delegates. Most importantly, Tuttle announced that he had 
convinced Surgeon General Wyman to continue supporting spotted 
fever research until the nature of the disease was positively determined. 
This commitment, Tuttle noted, was well worth the cost of his trip, 
since it might stem the plunge of property values in the Bitterroot.^ 

The confusion generated by the conflicting reports of Wilson and 
Chowning, Anderson, Stiles, and Ashburn about the germ of spotted 
fever, and especially about the tick as a vector of the disease, had 
indeed jeopardized property values on the west side of the valley. This 
threat appeared just as the Bitterroot launched a major effort to expand 
its economy by developing an irrigation system that would open the 
benchlands— the dry shores of the ancient lake bed— to cultivation. 
Since the mid 1890s, valley residents had sold their apples commer- 
cially, claiming that the climate in the Bitterroot was ideal for producing 
the tart, flavorful Mcintosh Red apple. In a period before dry farming 
was employed, however, the waterless bench lay barren. In 1905 a 
group of Chicago financiers developed a scheme to irrigate west side 
benchlands, a plan that was soon expanded into an enormous irrigation 
project to bring water to the east side bench as well. Locally the 
proposed irrigation canal and flume were called the Big Ditch. Ad- 
vertising in Chicago newspapers, the plan's promoters offered potential 
buyers a bearing orchard and a contract with Bitterroot citizens who, 
during the first five years of ownership, would tend, harvest, and market 
the apples for 10 percent of the net profit. By 1907 land in the Bitterroot 
was selling for $100— $150 an acre.^ 

Spotted fever represented a distinct menace to this enterprise, which 
was expected to swell the population of the Bitterroot nearly tenfold 
as new orchards came under cultivation. Since scientific research had 
produced no cure and much confusion, local Bitterroot boosters 
adopted the tactic of officially ignoring the disease's existence. Begin- 
ning in 1904, newspapers rarely mentioned spotted fever in obituaries, 
usually describing it as fever or a brief illness. Distinguishing spotted 
fever cases from other maladies in news accounts thus became much 
more difficult. Only the time of year and the duration of the disease 
provided clues. Because few states at this time monitored any but the 
most contagious diseases, the Bitterroot Valley suffered no official 
reprimand for such action. Spotted fever was not one of the reportable 
diseases— those, such as diphtheria, smallpox, and typhoid fever, that 
physicians were obligated to report to state health authorities. Vital 
statistics on births and deaths in the state were not even required to 



Dr. Ricketts's Discoveries 



49 



be collected until mid 1907, and Montana preceded many other states 
in that endeavor."^ 

Despite this vote of no confidence in science by local residents, in 
1905 research into spotted fever reached a turning point. Montana 
Congressman Joseph M. Dixon and the State Board of Health secretary, 
Thomas D. Tuttle, held Surgeon General Walter Wyman to his promise 
to continue investigating the disease. Tuttle sent a written request and 
Dixon visited the surgeon general. At the beginning of May, Edw^ard 
Francis, a Hygienic Laboratory physician v^ho had contributed to the 
Service's study of yellow^ fever in Vera Cruz, Mexico, v^as detailed to 
Montana.^ Fifteen years later, Francis w^ould make a significant con- 
tribution to the understanding of tularemia, another disease of nature 
found in the Bitterroot and in other areas, but in 1905 his research 
on spotted fever produced no significant results. Although he corrob- 
orated Stiles's findings that no Piroplasma was present, Francis was 
unable to throw further light on the etiology of the disease and never 
published an account of his work.^ These negative findings, however, 
indicated that the next spotted fever experiments must move in a 
different direction if they were to be productive. 

In November 1904, Charles Wardell Stiles unwittingly fueled this 
fire when he delivered the Middleton Goldsmith Lecture, an address 
published in early 1905 in the highly respected and widely read sci- 
entific journal. Proceedings of the New York Pathological Society. 
Taking as his title, "Zoological Pitfalls for the Pathologist," Stiles 
cautioned pathologists to be careful about drawing zoological con- 
clusions if they were not thoroughly trained in zoology. He held up 
the Piroplasma theory of Wilson and Chowning as a case in point, 
and his refutation of their theories "savored of scorn," as one observer 
noted.^ 

Stiles's pointed and uncharitable remarks stung Wilson and Chown- 
ing, but they also stimulated the interest of other investigators in the 
debate over this mysterious disease. Louis B. Wilson abandoned spotted 
fever research in 1905 when he accepted a position at the Mayo Clinic. 
There he pursued a distinguished career as a pathologist and admin- 
istrator. William M. Chowning, however, continued spotted fever in- 
vestigations while engaging in his newly established private surgical 
practice. He hoped to justify his earHer work and produce an antitoxin 
for spotted fever. In early 1906, Chowning corresponded with Howard 
Taylor Ricketts, a pathologist at the University of Chicago, who was 
interested in beginning his own investigation of spotted fever. Although 
Chowning had hoped that the two might work together despite Stiles's 
adverse criticism, Ricketts stipulated that his would be an independent 



50 



Rocky Mountain Spotted Fever 



study. "I may say," Ricketts wrote, "that it was exactly this criticism 
of Stiles which gave me the idea of going to Montana to study spotted 
fever. I was not at all pleased with the tone of his criticism as it was 
presented to the New York pathological society, and it occurred to 
me that this would be a good time for a third party to go into the 
field and repeat the ground covered by yourself and Wilson."^ 

Chowning also revealed that he had "experimentally reproduced" 
spotted fever in a human in Minneapolis and was presently "watching 
another similar inoculation." The material used "was a blood (defi- 
brinated) culture from a Montana case (fatal)." The first experimental 
case was recovering; the second was too recent to predict. Ricketts 
made no comment to Chowning about the human experiments, and 
Chowning never published the results of this daring and ethically 
questionable investigation. Neither of them knew that Idaho physicians 
had also conducted tick transmission experiments on humans. The 
ticks used, however, were infected with the mild Idaho strain of the 
disease, not the fatal Bitterroot strain Chowning used. Although this 
study was not pubhshed until 1908, Lucien P. McCalla and his col- 
league H. A. Brereton had in May 1905 obtained permission from 
two patients, one male and one female, to attach to each a tick that 
had been affixed to a patient suffering from Idaho spotted fever. Both 
patients became ill with the disease and both recovered.^ 

Ricketts was undoubtedly interested in Chowning's proposed an- 
titoxin against spotted fever, for this was an area in which Ricketts 
had just published a major textbook, Infection, Immunity, and Serum 
Therapy. This promising young researcher, born in Findley, Ohio, in 
1 871, had taken his undergraduate degree at the University of Ne- 
braska, where he studied zoology with the distinguished animal par- 
asitologist Henry B. Ward. In 1894 he had entered Northwestern 
University School of Medicine in Chicago as a member of the second- 
year class because of his soHd undergraduate preparation, a criterion 
many of his classmates lacked. ^° Despite a nervous breakdown from 
overwork and constant financial problems— his family had lost its 
fortune in the panic of 1893 —Ricketts had excelled and graduated in 
1897, winning an internship at Cook County Hospital. In 1900 he 
became a fellow in pathology and cutaneous diseases at Rush Medical 
College in Chicago, where he accomplished his first important research, 
a study of blastomycosis, the first disease known to be produced by 
a yeast. 

This work brought him to the attention of Ludvig Hektoen, who 
was shortly to become chairman of the Department of Pathology and 
Bacteriology at the University of Chicago and director of the John 



Dr. Ricketts's Discoveries 



51 



Howard Taylor Ricketts of the 
University of Chicago designed 
the experiment that first demon 
strated tick transmission of 
Rocky Mountain spotted fever. 
Ricketts's contributions to the 
understanding of spotted fever, 
including identification of the 
causative organism, were later 
recognized when the microorga 
nisms that cause spotted fever 
and related diseases were desig- 
nated Rickettsiae in his honor. 
Ricketts died in 19 10 during a 
study of epidemic typhus in 
Mexico. (Courtesy of the Na- 
tional Library of Medicine.) 

Rockefeller McCormick Memorial Institute for Infectious Diseases. At 
Hektoen's suggestion, Ricketts spent a year abroad, in Berlin, Vienna, 
and Paris, where he perfected his laboratory technique and broadened 
his understanding of theoretical microbiology. Upon his return in 1902 
he was appointed instructor in Hektoen's department at Chicago. With 
the publication of his book in 1906, Ricketts had established his rep- 
utation as a rising scientific star. 

Since Montana had appropriated no additional monies in 1906 for 
spotted fever investigations, the three researchers who appeared in the 
field that year had to supply their own funds. Ricketts obtained a small 
grant from the Committee on Scientific Research of the American 
Medical Association (AMA) to defray his expenses. He arrived on 21 
April at the Northern Pacific Hospital in Missoula and, at the invitation 
of the chief surgeon, E. W. Spottswood, erected laboratory and personal 
housing tents on the hospital grounds. William M. Chowning also 
worked in the field at his own expense, Hmiting his research to mi- 
croscopic analysis of the blood of spotted fever victims. Having ap- 
parently abandoned the Piroplasma theory, Chowning focused instead 
on what he described as "a myriad of fantastic but highly deceptive 
forms," which he classified as fungi. 




5 2 Rocky Mountain Spotted Fever 




Interior of Howard Taylor Ricketts's tent laboratory, erected in 1906 in 
Missoula, Montana. (Used by permission of the Department of Special 
Collections, University of Chicago Library.) 



Joining Ricketts and Chowning in late April was Walter W. King 
of the U.S. Public Health and Marine Hospital Service, who, fresh 
from five years' service as chief quarantine officer in Puerto Rico, had 
been sent by Surgeon General Wyman to continue the Service's in- 
vestigation of spotted fever. In Puerto Rico, King and a U.S. Army 
physician, Bailey K. Ashford, had demonstrated that a severe anemia 
found on the island was caused by the American species of hookworm 
identified by Charles Wardell Stiles. As members of an anemia com- 
mission established in 1904, King and Ashford had worked with a 
Puerto Rican physician, Pedro Gutierrez, to develop a treatment pro- 
gram that reduced the death rate from 30 percent to less than i 
percent. 

Despite King's experience in public health work, Ricketts took con- 
trol and directed the experimental work from the outset. King noted 
that Ricketts's "education for the work was very thorough," and that 



Dr. Ricketts's Discoveries 



53 



he "looked at things in a big way," always going "straight to the grist 
of the matter." Ricketts's ability to conceptualize experiments that 
others could not, or had not, perhaps best reflects the impact of his 
training with leading European bacteriologists, for the actual tech- 
niques available to researchers were at that time quite simple. Pure 
strains of bacteria were obtained by culturing them on solid gelatin 
media. Experimental animals provided a means to isolate pathogenic 
bacteria from a sick animal as well as to show that a bacterial culture 
would produce a particular disease. In order to see microorganisms 
under the microscope— itself an indispensible bacteriological tool— 
common dyes and special stains were used on blood and tissue smeared 
on glass slides. 

A rudimentary knowledge of biochemical reactions faciHtated the 
physiological study of bacterial metabolism, and theories of immunity 
informed attempts to produce vaccines, antisera, and diagnostic tests. 
The agglutination test, for example, was generally considered a reliable 
indicator of the presence of particular disease organisms. Blood was 
typically drawn from a person recently recovered from a disease, and 
a procedure known as defibrination was employed to speed clotting. 
After the clot was removed, the blood was centrifuged to separate the 
solid cells from the liquid. To the serum were added organisms sus- 
pected of causing the disease. The serum of the recovered patient 
contained antibodies, proteins produced by the body in response to 
the presence of foreign proteins, or antigens. Since antibodies bind to 
their complementary antigens, the serum would clump or agglutinate 
if the patient had suffered from the disease caused by the suspect 
organisms. Although exceptions were possible, such a reaction pro- 
vided strong evidence for the presence of the disease under suspicion. 

Skilled in such methods, Ricketts had already begun a microscopic 
study and culture experiments, and he was outlining future experiments 
by the time King arrived. Since Ricketts could find neither Piroplasma 
nor bacteria in the blood, and King's independent study confirmed 
that none was present, it seemed clear that the spotted fever organism 
was of a type that could be studied only in an experimental animal. 
Both Ricketts and King thus turned their energies to identifying an 
animal in which the disease could be easily recognized. Ricketts first 
attempted to inoculate rabbits with infected blood, but the results were 
inconclusive, two animals showing no signs of illness and a third only 
a slight fever. If readily available rabbits were unacceptable models, 
funds would be needed to purchase other laboratory animals until a 
good model was identified. To this end, E. W. Spottswood addressed 
the Missoula Chamber of Commerce on 1 5 May, and nine days later 



54 



Rocky Mountain Spotted Fever 



the Missoula County commissioners appropriated one hundred dollars 
to fund the purchases. The Montana State Board of Health secretary, 
Thomas D. Tuttle, contributed an additional forty dollars from the 
board's appropriation.^^ 

Ricketts and King worked independently, but they shared the small 
amount of blood available from spotted fever victims as they inoculated 
guinea pigs, monkeys, w^hite rats, and mice purchased with the ap- 
propriated funds. Since the most favorable route for inoculation was 
unknown, the two men drew lots for subcutaneous and intraperitoneal 
injections. As it happened, both routes proved successful. Only the 
guinea pigs and monkeys, however, displayed a definitive feverish, or 
febrile, reaction. The less expensive guinea pig proved an ideal model 
of the disease in humans. It ran a marked fever, and the males displayed 
a swollen scrotum that became a characteristic sign of spotted fever 
infection. When Ricketts attempted to maintain the disease in guinea 
pigs, however, he had difficulty, but he was able to sustain the infection 
in animals by alternating injections in monkeys and guinea pigs. This 
achievement had far-reaching implications. It meant that he could study 
the disease year round, making research independent of the incidence 
of spotted fever cases. Identifying an acceptable, inexpensive experi- 
mental animal was, in Ricketts's evaluation, the most important work 
accomplished that spring. 

Once the reaction of guinea pigs was known to be a reliable indicator 
that the disease was present, Ricketts conducted experiments to de- 
termine whether the infectious agent was a microbe or a toxin and 
whether it was confined to the red blood cells of victims or was trans- 
mitted also by the serum of the blood. Short on blood from spotted 
fever victims, Ricketts discovered by chance on ii June that a nine- 
year-old girl, Etta Bradley, was severely ill with the disease near 
Stevensville.^^ From her he obtained 60-70 cc of blood, some of which 
he centrifuged to separate the heavier red and white cells from the 
hghter serum. The solid cells were washed to remove any remaining 
serum, and samples of the serum and washed cells were injected into 
guinea pigs. Some of the serum, moreover, was passed through a 
ceramic Berkefield filter at low pressure. The small pores of such filters 
obstructed the passage of most microorganisms, but toxins and so- 
called filterable viruses passed through unimpeded. This filtered serum 
was also injected into a guinea pig. 

All the guinea pigs suffered a fatal infection except for the one 
injected with filtered serum. This indicated that the infectious agent 
was not a toxin or filterable virus and that the microbe trapped by 
the filter should be large enough to be seen under a microscope. In 



Dr. Ricketts's Discoveries 



55 



addition, the infectiveness of both blood corpuscles and unfiltered 
serum demonstrated that the spotted fever microbe was not localized 
in one part of the body, as was true in tetanus, but rather circulated 
in the blood. The finding that serum was infective threw further doubt 
on Wilson and Chowning's Firoplasma theory, because those or- 
ganisms were found almost exclusively in red blood cells. 

Ricketts sent a manuscript describing these experiments to the Jour- 
nal of the American Medical Association^ which published it in the 
issue of 7 July. Although these preliminary experiments were vital in 
making further work possible, they did not yet answer the question 
burning in everyone's mind: Was this spotted fever microbe transmitted 
by the bite of a tick? Both Ricketts and King began tick transmission 
experiments just as their stay in Montana ended. They fed ticks on 
infected guinea pigs and placed them on healthy guinea pigs. Both 
researchers got positive results from their experiments— thus dem- 
onstrating for the first time that a human disease in the United States 
could be transmitted by a tick. After returning to their laboratories in 
Chicago and Washington, Ricketts and King prepared papers on the 
experiment. King's paper, "Experimental Transmission of Rocky 
Mountain Spotted Fever by Means of the Tick," however, was pub- 
lished in the Public Health Reports eight days before Ricketts's paper 
on the subject appeared in the Journal of the American Medical As- 
sociation.^^ 

Having spent a good deal of his own money to finance the research 
as well as having conceived the experiment, Ricketts was annoyed at 
King's priority in pubHshing on this important question. "In view of 
the result which I had obtained," Ricketts wrote in his article, "I was 
not surprised to note the recent report of Dr. King, . . . who, starting 
with material which I had given him, accomplished transmission in 
the same manner."^^ Ricketts had already complained to the secretary 
of the Montana State Board of Health, Thomas D. Tuttle, about the 
necessity of several researchers sharing the limited quantity of available 
spotted fever blood. Admitting that it was "a little bit selfish on my 
part," Ricketts requested Tuttle to "Hmit the number of workers" on 
spotted fever in the Bitterroot the following season, a plea Tuttle had 
no power to enforce.^^ The incident with King caused Ricketts to 
exercise much more caution in sharing material or reveaHng the results 
of his research before publication.^^ 

The results of the 1906 work infused new life into spotted fever 
investigations. In the same issue that announced the enactment of the 
first federal pure food and drugs law, the journal of the American 
Medical Association commented editorially that Ricketts's and King's 



56 



Rocky Mountain Spotted Fever 



"extremely interesting and important work" would provide "a new 
impetus" to spotted fever research. Reflecting prevailing assumptions 
about arthropods and the types of organisms they might transmit, the 
editorial also observed that further experiments were necessary "to 
determine whether the infecting organism must undergo a cycle of 
development, as in the case with some organisms, notably the Plas- 
modium malariae.'''^'^ 

The secretary of the Montana State Board of Health was jubilant 
over Ricketts's discoveries but dismayed that the state legislature had 
not supported the undertaking financially. In his summary of the 1906 
work. Turtle remarked sarcastically that the "magnanimous" contri- 
bution of the state toward the purchase of experimental monkeys 
amounted to "the extravagant expenditure of forty dollars." To con- 
tinue the work properly, he stated, the legislature should appropriate 
not less than fifteen hundred dollars, and preferably two thousand 
dollars. Ricketts had also urged the state to appoint a legislative study 
committee and to appropriate sufficient money to continue the inves- 
tigation when he spoke in May 1906 at the Montana Medical Asso- 
ciation.^^ 

In his annual report, moreover, Tuttle broadened his crusade for 
increased funding to public health in general. He noted that the $2,000 
budget of the state board of health was paltry compared to the generous 
increases given to other state boards— Massachusetts, for example, 
expended $96,500 per year; Minnesota, $20,000 per year; and even 
scantily populated Colorado, $5,000 per year. Raising the question of 
whether the legislature considered the life of a Montanan to be worth 
as much as that of a Bostonian, Tuttle challenged the lawmakers to 
increase funding for all public health measures, including spotted fever 
research. This emotional appeal apparently swayed state legislators, 
because they appropriated $2,000 for further work by Ricketts during 
1907.^^ 

The additional funds were certainly welcome, because the work of 
1906 opened a promising new direction for spotted fever investigations 
that would require much additional research before the disease could 
be prevented or treated. The tick transmission experiments had to be 
repeated, since Ricketts and King had infected only a single guinea pig 
each. Furthermore, proof that the tick could transmit the disease in 
the laboratory did not demonstrate that infected ticks existed in nature. 
If such ticks did exist, virtually nothing was known about their life 
cycle or about the hosts from which they might contract the infection. 
In addition, although Ricketts had postulated that a visible microbe 



Dr. Ricketts's Discoveries 



57 



might cause the disease, no one had yet been able to locate it under 
the microscope or culture it in the laboratory.^' 

During the fall and wmter of 1906-7, King and Ricketts continued 
their research on spotted fever in Washington and in Chicago. To 
enable their experiments to go forward, both needed a continuous 
supply of ticks. Each wrote to contacts in the Bitterroot, who enlisted 
local newspapers to advertise for people to collect ticks. Locating ticks 
after they disappeared in mid summer, however, was an almost im- 
possible task. The Western Neivs, believing that it was "worth some- 
thing" to discover "where the ticks are in the winter," offered ten 
dollars in gold to the first person bringing "50 or more live, able- 
bodied ticks" to the newspaper office between 29 November and 15 
December 1906. Even with this financial incentive, local tick sleuths 
were apparently baffled. No report announced that the gold had been 
claimed, and in mid December the paper advertised for ticks again, 
offering "two bits per head" for any number of able-bodied ticks,^^ 

With the few ticks he was able to obtain, Ricketts continued his 
experiments in Chicago, where he was promoted to assistant professor 
in the Department of Pathology- and Bacteriolog)^^^ Using a wire mesh 
collar he had designed to hold ticks in place on the guinea pigs, Ricketts 
conducted experiments to demonstrate that male as well as female 
ticks could transmit the disease. He had also hoped to settle the question 
of whether female ticks transmitted the spotted fever organism to their 
offspring. Unfortunately, the ticks failed to breed, so the experiment 
was postponed until the following spring. One major success crowned 
Ricketts's efforts during the cold Chicago winter: he solved the problem 
of how to preserve the spotted fever strain in guinea pigs alone. He 
had, of course, already managed to maintain the infection by alter- 
nating inoculations between guinea pigs and monkeys, but monkeys 
were expensive. In his first attempts with guinea pigs, Ricketts had 
taken blood from a dead or dying pig and inoculated it into a fresh 
one. The infectious agent, he discovered by repeated experiments, was 
most virulent during the height of the disease. With this information 
he was able to perpetuate the infection in guinea pigs alone by utilizing 
blood from a sick but not moribund guinea pig.^° 

Ricketts began the new season's work with the strain of spotted 
fever he had successfully sustained in guinea pigs. This proved for- 
tunate, for spotted fever cases occurred only sporadically, and the 
famihes of victims did not always welcome a doctor whose primary 
interest was research. In 1907 the first case of spotted fever did not 
appear until mid April. It struck a twent>'-six-year-old lumberman, 



58 



Rocky Mountain Spotted Fever 



Maurice J. Holden, who was secretary-treasurer at the Florence lodge 
of the International Workmen of the World. Ricketts visited the patient, 
but Holden's family "objected to a thorough examination" and refused 
to allow Ricketts to draw any blood. When Ricketts apprised Turtle 
of this situation, the secretary of the state board of health prepared 
an official-looking document instructing local people to cooperate with 
the investigation. He admonished Ricketts, however, not to present 
the document "where people are liable to look into it too closely," 
because in truth "we have no authority" to issue it.^^ 

Walter W. King also returned to the Bitterroot in the spring of 1907, 
as did William M. Chowning, who continued to study the variety of 
organisms he found in spotted fever blood. Ricketts and King resumed 
their studies, jointly visiting cases and drawing blood. Wary of King's 
competition, however, Ricketts conducted his experiments alone. 
"King and I have had no difficulty so far," Ricketts wrote to Ludvig 
Hektoen, but he characterized King as having "many questions to ask 
in his smooth 'governmental' fashion. "^^ 

Ricketts worked intensely on the question of whether female ticks 
could transmit spotted fever to their offspring. He worried that King 
might again publish first on this important question. In a letter to 
Hektoen, Ricketts noted that King had "sent ripened females to Wash- 
ington," where "doubtless" King's colleagues would soon be "at work 
on these points." Ricketts's assistants also collected ticks from known 
spotted fever locales for experiments to determine if infected ticks 
existed in nature. Describing this work to Hektoen as the most im- 
portant of all, Ricketts emphasized that this experiment in particular 
was the one he wanted "to get into print as soon as possible." Although 
King appeared to be conducting only small-scale research on this prob- 
lem, Ricketts feared that it might be "just his luck" for King to get 
the answer first.^'* 

For all Ricketts's foreboding, however. King's 1907 work resulted 
in no publications, and shortly after King returned to Washington, 
D.C., he was detached from the Hygienic Laboratory and ordered to 
San Francisco for duty. Since the laboratory director, Milton J. Ro- 
senau, retained only the Service's most promising research scientists 
on his staff, it is possible that King's failure at least to match Ricketts's 
achievements indicated to Rosenau that King was more suited for other 
types of work. After leaving spotted fever investigations. King returned 
to his work as a quarantine officer, serving at San Francisco, Ellis 
Island, and Naples, Italy.^^ 

After the 1907 spotted fever season, Ricketts had the field virtually 
to himself. His research was conducted on a variety of fronts, including 



Dr. Ricketts's Discoveries 



59 



efforts to identif)^ the spotted fever organism and experiments with a 
potential antiserum and a vaccine against spotted fever. Reahzing that 
effective therapeutic measures might take a number of years to develop, 
Ricketts devoted much of his time in 1907 and 1908 to understanding 
the relationship between spotted fever and the tick. Such knowledge, 
he hoped, would provide the basis for developing a practical program 
for controlling the tick, thereby reducing the incidence of the disease. 

The question of possible hereditary transmission of the spotted fever 
organism was of vital importance. With the assistance of two students, 
Paul G. Heinemann and Josiah J. Moore, Ricketts devised an exper- 
iment in which sixty female ticks were fed on infected guinea pigs and 
then allowed to breed. Of these, twenty-six produced eggs. The larvae 
produced by each female were then placed on a healthy guinea pig to 
see if spotted fever had been transmitted to them by their mothers. 
The results of this tedious process, which required meticulous handling 
and record-keeping at each stage, were somewhat surprising. Of the 
twenty-six groups of larvae, only two infected the guinea pigs on which 
they fed. "If this was the result in twenty-six laboratory experiments," 
Ricketts wrote, "it is fair to conclude that . . . only a small percentage 
of infected females passes the disease on to their young" in nature. 
When Ricketts and his part-time colleague Maria B. Maver repeated 
these experiments, they achieved somewhat higher percentages of 
transmission.^^ The results were clear, however: hereditary transmis- 
sion did occur, but only in a minority of cases. This finding, coupled 
with additional research that showed the salivary glands of the tick 
also to be infective, led Ricketts to conclude that spotted fever was 
probably a generahzed infection of tick tissues that was transmitted 
biologically by the tick through biting.^" 

Determining whether infected ticks existed in nature— the work that 
Ricketts had been so anxious to publish— was likewise a tedious pro- 
cess. Each year from 1907 to 1909, Ricketts collected ticks and watched 
to see if any guinea pigs on which they fed became ill. As in the 
hereditary experiments, Ricketts found that only a small number of 
ticks contained the virulent organism, because most of the guinea pigs 
remamed healthy. Convinced at last that his work was definitive, Rick- 
etts wrote to Tuttle that three years of experiments should be "enough 
to prove to the satisfaction of everyone that infected ticks do occur 
naturally" but in small numbers. 

Having determined that the Rocky Mountain wood tick carried 
spotted fever, Ricketts assigned Maver the task of determining whether 
other ticks could carry the infection as well. Initially, Maver dem- 
onstrated that the tick carrying the mild Idaho spotted fever could 



6o 



Rocky Mountain Spotted Fever 



also transmit the virulent Bitterroot Valley strain and, conversely, that 
the tick found in the Bitterroot could transmit the mild Idaho strain 
of the disease. During the summer and fall of 1909, Maver began 
experiments with the dog tick common to the eastern United States, 
the "lone star" tick common on cattle from Missouri to Texas and 
Louisiana, and a rabbit tick from Utah. All three ticks transmitted 
spotted fever to guinea pigs. "From these experiments," Maver w^rote, 
"it appears that . . . the disease might find favorable conditions for 
its existence in localities other than those to which it now is limited." 
At this time there was concern that spotted fever might spread within 
the western United States but no indication that it might exist in other 
parts of North America. 

The life cycle of the Rocky Mountain wood tick was another problem 
to be solved before tick control could be implemented. From his brief 
observations over a single year, Ricketts provided an initial description 
of how ticks reproduced. After fertilization, which occurred on large 
host animals such as cattle and horses: 

the female continues to feed for several days . . . and during this time enlarges 
very rapidly, until she is finally transformed into the large gray or slate colored 
tick. On the other hand, the male, after prolonged feeding, undergoes no more 
enlargement than would be caused by the distension of a good feed. The 
enlargement of the female is due partly to the quantity of blood it has ingested, 
but, in addition, the change is to be looked on as sexual. The ovaries become 
greatly developed and hundreds or even thousands of minute eggs begin their 
rather slow formation. 

When the female has reached its greatest degree of enlargement, it drops 
from the animal and, after a rest of about two weeks or longer in cold weather, 
begins to lay eggs. The eggs are withdrawn from the anterior end of the lower 
surface of the body, the head parts assisting in their extrusion, and they 
accumulate in small masses on the back of the head. As their bulk becomes 
heavy they fall off and are replaced gradually by a second mass. This process 
continues until all the eggs, which may number several hundred or even two 
or three thousand, lie in a heap before the tick. In the meantime the female 
becomes greatly flattened and wrinkled and, in a comparatively short time 
dies. A female which has laid eggs never again assumes the appearance of the 
young red female and her life is ended in one season. 

The newly hatched six-legged larvae, Ricketts believed, fed on small 
animals, molted into eight-legged nymphs, and fed again. The nymphs 
then molted into sexually mature adults. Ricketts could not determine 
precisely how long this process took but noted that it was possible to 
speed it up in the laboratory by using incubators and providing im- 
mediately available hosts for each stage. He believed, however, that 
eggs deposited one year became adults capable of reproducing during 
the following spring."^^ 



Dr. Ricketts's Discoveries 



6i 



Working from an assumed twelve-month life cycle, which later 
would be shown to be incorrect, Ricketts attempted to formulate a 
program for control of the tick. Other arthropod-borne diseases that 
served as models for this effort were malaria, yellow fever, and Texas 
cattle fever. Yellow fever control efforts had clearly demonstrated that 
the Anopheles mosquito needed only to be reduced to a certain level 
to control the disease; it did not have to be eHminated."^^ Since Ricketts 
had already demonstrated that the percentage of ticks in nature infected 
with spotted fever was small, diminishing the total tick population 
promised a significant reduction in spotted fever cases. 

One key intervention strategy was preventing adult ticks from reach- 
ing the large animals on which they fed and mated. If this could be 
accompHshed, subsequent generations of ticks would never be born. 
The Texas cattle fever tick had been virtually eliminated by this method. 
Because that tick remained through its entire life cycle on a single 
animal, it had been possible to create tick-free pastures simply by 
removing stock. Ticks remaining on the ground starved for lack of a 
host. Once a pasture had been purged of ticks, stock from which all 
ticks had been carefully removed could be safely returned. A few years 
of alternating pastures in this manner effectively eliminated the Texas 
cattle fever menace. A second approach to tick control consisted of 
oiling the bodies of stock by hand or by dipping them in large vats 
several times during tick season. Oil was repugnant to ticks, repelling 
unattached ticks and causing those already attached to lose their hold. 
According to the Bureau of Animal Industry, moreover, oiling pro- 
duced no permanent injury to the cattle and horses. 

Ricketts corresponded about these methods with an entomologist 
at the University of Tennessee Agricultural Experiment Station, H. A. 
Morgan, who had a great deal of experience in the control of Texas 
cattle fever. Because the spotted fever tick had different hosts at each 
stage of its life cycle, Morgan doubted that alternating pasturage would 
be effective. In his report to the Montana State Board of Health, 
therefore, Ricketts recommended that the state undertake a program 
of oiling to reduce the tick population in settled areas. "Total exter- 
mination of the tick cannot be promised or expected," Ricketts wrote, 
since wild animals in the mountains would continue to act as hosts. 
"But this does not mean that the territory inhabited by the residents 
must continue to be infested with ticks. '"^'^ 

These preliminary recommendations, which included the admoni- 
tion that citizens also rid their premises of the ground squirrels that 
served as hosts to immature states of the tick, were based on the scanty 
information about the life cycle of the tick that Ricketts was able to 



62 



Rocky Mountain Spotted Fever 



gain in a few months' time. He advised that additional observations 
should be carried out year round, and he recommended entomologists 
M. J. Elrod of the University of Montana and Robert A. Cooley of 
the Montana State College as potential candidates. In 1908, Cooley, 
w^hose work will be discussed in chapter 5, took up the study. 

The first of two reports Ricketts prepared was written in a popular 
style and widely disseminated because many people in the Bitterroot 
continued to doubt the tick theory of spotted fever transmission. "It 
is absolutely necessary," Ricketts noted, for Bitterroot residents "to 
know something about the life history of the tick and its bearing on 
the question if they are to accept the tick theory.'"^^ Thus, in addition 
to his formal recommendations, Ricketts included practical informa- 
tion on dealing with tick bites. Countering superstitions about how 
one must approach an attached tick, Ricketts stated: "The tick, if 
attached, should be removed immediately, not by attempting to 'un- 
screw' it as is so often recommended, but by grasping the body firmly 
and pulling gently and continuously. ... A sudden jerk is likely to 
tear the body from the head, leaving the latter imbedded in the skin. 
A drop of kerosene oil will cause the animal to loosen its hold.'"^^ 

He also advised those bitten not to apply carboHc acid with the 
stopper of the bottle or by inverting the bottle over the wound. Such 
a procedure, Ricketts warned, was "both inefficient and dangerous" 
because it burned an excessive area of the skin. The actual point at 
which the tick inserted its fine toothed proboscis into the skin and 
deposited the spotted fever organisms was small. "The proper method 
of applying the carbolic acid," therefore, was "to dip a sharp pointed 
toothpick or splinter of wood into the acid . . . and then to thrust the 
tip deeply into the point of the bite, twisting the wood as it penetrates." 
The first application was rather painful, Ricketts admitted, but the 
acid had a tendency to destroy the sense of pain, and the second and 
third applications immediately following would cause only "a small 
degree of discomfort.'"^^ 

Even this recommended method, however, carried no guarantee 
since, as Ricketts observed, "we have, as yet, no experimental evidence 
to show just how effective cauterization of the tick wound with carbolic 
acid is in preventing spotted fever." He doubted that any treatment 
was effective if the tick remained attached for several hours. "The 
virus in a short time probably extends too far for the acid to have any 
effect on it," he stated. Later experiments by his student, Josiah J. 
Moore, indeed demonstrated that within two hours, an attached tick 
could inject enough spotted fever organisms to cause the disease."*^ 

Opinion remained divided in the Bitterroot about the tick theory, 



Dr. Ricketts's Discoveries 



63 



but businessmen supported Ricketts and hoped his findings could be 
used to stabihze land prices. In June 1907 a "woodtick dance" at 
Florence raised funds for burning brush in which ticks were plentiful. 
Real estate salesmen promoting sweet and sour cherries as well as 
apples to Chicago clients sought to minimize the impact of spotted 
fever on land sales with tangible proof that the entire valley was not 
affected. A representative of the Bitter Root Valley Irrigation Company 
asked Tuttle, the secretary of the state board of health, if he and Ricketts 
would prepare a joint statement that the west side of the valley alone 
was infected. The company planned to publish this document "for the 
purpose of furthering the sales of land." Ricketts and Tuttle complied, 
with the stipulation that their names be used "with due modesty and 
discretion. "^° 

Although his plan to control ticks was of paramount importance, 
Ricketts also pressed forward in a number of other areas. One was 
identifying the elusive spotted fever organism. From the beginning of 
his work, Ricketts had tried to culture a bacterium with no success, 
although his filtration experiments had convinced him that the germ 
must be large enough to see with a microscope. He tried various staining 
methods, including the Giemsa and Levaditi stains, considered best 
for reveahng parasites in the blood. With the Giemsa stain — the world's 
standard diagnostic agent for malarial organisms — Ricketts consist- 
ently found "small spherical, ovoid and diplococcoid forms," which 
seemed to be bacteria. To prove bacterial causation according to Koch's 
postulates, however, Ricketts had to culture the organisms on artificial 
media. Despite repeated attempts, he had not been successful.^^ 

Ricketts therefore declined to publish a claim that the diplococcoid 
bodies were the cause of spotted fever. Prevailing scientific opinion, 
moreover, continued to support the belief that arthropods transmitted 
only protozoan organisms biologically. In a 1908 article reviewing the 
state of knowledge of ticks and disease, W. A. Hooker of the U.S. 
Bureau of Entomology outHned the piroplasmic diseases carried by 
ticks. Although he noted that the spotted fever organism remained 
unidentified. Hooker's evidence lent credence to the hypothesis that 
spotted fever would probably also be a Piroplasma or Spirilla — or- 
ganisms known to be transmitted by ticks. Two years later, Rennie 
W. Doane, an assistant professor of entomology at Leland Stanford, 
Jr., University, pubhshed a popular book entitled Insects and Disease, 
in which he argued that, among parasitologists, spotted fever was 
"quite generally believed" to be carried by some sort of protozoan 
organism. 

Nonetheless, by January 1909, Ricketts was convinced that he had 



64 



Rocky Mountain Spotted Fever 



indeed identified the spotted fever microbe. His published description 
of the bacillus was conservatively entitled "A Micro-Organism Which 
Apparently Has a Specific Relationship to Rocky Mountain Spotted 
Fever: A Preliminary Report." He characterized the organism as "a 
bipolar staining bacillus of minute size, approximating that of the 
influenza bacillus [s/c], although definite measurements have not yet 
been made." Agglutination experiments w^ith the bacillus in tick eggs 
produced no reaction v^^ith the blood of normal guinea pigs, but the 
blood of immune guinea pigs — those w^hich had recovered from a bout 
with spotted fever— produced the "striking result" of complete agglu- 
tination in dilutions of up to i to 320. "In so far as I know," Ricketts 
wrote, "it would be an unheard-of circumstance to obtain such strong 
agglutination with an immune serum, in the presence of negative con- 
trols, unless there were a specific relationship between the organism 
and the disease. "^^ 

Noting that he had employed rehable staining methods in searching 
for presumed Piroplasma or Spirilla, moreover, Ricketts argued that 
the organism of spotted fever showed bacterial, not protozoan, char- 
acteristics. In addition, he reiterated Charles Wardell Stiles's clinical 
findings that clearly differentiated spotted fever from the piroplas- 
moses.^"^ "That a bacillus may be the causative agent of a disease in 
which an insect carrier plays an obligate role under natural conditions 
may be looked at with suspicion in some quarters," he observed, 
anticipating the reaction his preliminary communication might bring. 
"Yet ... it would seem to be unscientific," he admonished his col- 
leagues, "to be tied to the more or less prevailing belief that all such 
diseases must, on the basis of several analogies, be caused by parasites 
which are protozoon in character."^^ 

Ricketts was cautious in his pubhshed statements, but to his friends 
he revealed complete assurance. "Just a note to tell you that I have 
found the microorganism of spotted fever," Ricketts wrote to Tuttle 
just before the JAMA article was published. "The eggs of infected 
female ticks are loaded with them," he added, describing the organism 
as "similar to the plague bacillus" but smaller. A distinguished Mich- 
igan bacteriologist, F. G. Novy, who had corresponded with Ricketts 
about staining techniques during his research, congratulated Ricketts 
and observed that the tick-bacillus connection, if proven, would over- 
turn existing beliefs about arthropod vectors: "If you can clinch the 
story it will be a fine one which will kind of upset some of our cock- 
sure friends." WiUiam M. Chowning, still unforgiving about Stiles's 
ridicule of his earlier work, was "more than pleased" that Ricketts 



Dr. Ricketts's Discoveries 



65 



had "placed the problem where Stiles will be compelled to backwater 
again."^^ 

Feeling certain that he had identified the spotted fever organism, but 
also knowing that scientific proof as yet eluded him, Ricketts com- 
mented on his dilemma to Tuttle: "I remind you that we have not yet 
been able to cultivate [the microbe], and thus meet one of Koch's great 
laws. This makes it necessary to bring all kinds of indirect evidence 
to bear showing that we have the real thing." He promised Tuttle that 
the cultivation work would be continued until success was achieved 
"or until we have satisfied ourselves that it cannot be done." Ricketts 
placed much of the responsibiHty for these studies on Eugene Franklin 
McCampbell, a professor of bacteriology at Ohio State University, 
who in 1909 was a visiting lecturer at the University of Chicago. 
Interested in the challenge presented by this stubborn organism, 
McCampbell seemed to make headway against it; in November he 
wrote Ricketts that he had isolated a culture of the small diplobacillus 
that corresponded morphologically "exactly with that seen in the tick 
eggs and in the blood." It was so virulent, McCampbell claimed, that 
injections of water condensation in the culture tubes killed guinea pigs 
in twenty-four to thirty-six hours. Unfortunately, McCampbell did not 
describe his method, nor did he publish his results. 

Ricketts also utilized his specialized knowledge of vaccines and se- 
rum therapy in attempts to produce a prophylactic vaccine and a 
curative serum. As early as 1907 he had optimistically commenced 
vaccination experiments, "a la Pasteur." In using this phrase, Ricketts 
was referring to Louis Pasteur's empirical attenuation of the rabies 
virus by drying infected spinal cords of animals over a period of time, 
for no one had isolated the rabies pathogen when Pasteur worked. 
Assisted by his student Liborio Gomez, Ricketts similarly endeavored 
to attenuate the spotted fever organism. They desiccated it "over sul- 
phuric acid" and planned a series of injections that would use increas- 
ingly "smaller quantities of virus which had been dried for shorter 
periods, passing finally to minute amounts of fresh virus."^^ Unfor- 
tunately, this method did not work; the organisms were either killed 
outright or remained completely infective. 

Having determined that the minimum pathogenic dose of blood 
infected with spotted fever was between 0.0 1 and 0.03 cc for guinea 
pigs, Ricketts and Gomez next attempted to produce immunity by 
allowing animals to build up resistance to extremely small doses of 
the organism. This idea was also quickly abandoned. "As a rule," they 
noted, a minute quantity [of infected blood] either produces frank 



66 



Rocky Mountain Spotted Fever 



infection or causes no disturbance whatever. . . . On account of the 
uncertainty as to what the virus will do when injected in quantities 
which approximate the minimum pathogenic dose, it is manifest that 
minute doses cannot be utihzed for practical vaccination."^^ 

More promising experiments resulted from mixing small quantities 
of infected blood with "immune" blood — that is, blood from an animal 
that had recovered from spotted fever. Since it was known that a single 
infection with the disease produced lasting immunity— which was also 
passed to the offspring of immune females — Ricketts hypothesized that 
the immune blood would neutralize the live organisms sufficiently to 
prevent a fatal case of the disease and, at the same time, produce 
immunity in the inoculated animal. Experiments with guinea pigs dem- 
onstrated that this "sero-vaccination" was efficacious. Ricketts was 
cautious, however, about generalizing the findings from guinea pigs 
to humans. Observing that "the unknown susceptibility of man in 
comparison with that of the monkey and guinea pig" was a serious 
stumbling block to direct application of the technique to humans, he 
suggested, "Only one method could possibly be advocated at the outset; 
namely, to use such proportions of virus and immune serum as would 
leave no question as to the safety of the procedure, assuming for the 
time that the virus has the greatest possible virulence for man."^° 

Before this method could be pursued further, Ricketts made a dis- 
covery that stimulated a completely different approach toward pro- 
ducing a spotted fever vaccine. While examining the tissues and eggs 
of noninfective ticks used as controls in his experiments, Ricketts was 
astonished to find that many contained bacilli morphologically iden- 
tical to the virulent organisms in infective ticks. These bacilli, moreover, 
would also agglutinate immune serum but not normal serum. "I have 
come to the conclusion," he stated, "that avirulent strains of the spotted 
fever microbe are to be found in nature in the tick." He realized, of 
course, that this point must be proved "in order to have the microbe 
above reproach in the eyes of scientific critics," but he also viewed the 
avirulent organisms as potentially the "nucleus of a successful vac- 
cine."^i 

Ricketts asked Eugene Franklin McCampbell to conduct experi- 
ments on the vaccinating power of noninfective tick eggs. A shortage 
of guinea pigs slowed the new work to some extent, but results of 
initial experiments were promising. "We have a few experiments," 
Ricketts wrote to Ludvig Hektoen, "which indicate that vaccination 
takes place when the eggs or organs of ticks which contain avirulent 
bacilli are injected into guinea pigs." Ricketts hoped to bring this series 
of experiments to a conclusion during the winter of 1909—10.^^ 



Dr. Ricketts's Discoveries 



67 



At the same time, Ricketts also pursued the development of an 
antiserum for treating those already ill with the disease. Elie Metch- 
nikoff had pioneered serum therapy by producing an antitoxin in horses 
that would dramatically halt the ravages of diphtheria. Hoping to 
produce a similarly effective product for spotted fever, Ricketts began 
by "hyperimmunizing" a small group of guinea pigs and horses. This 
was accomplished by injecting an animal that had recovered from 
spotted fever— and thereby had achieved immunity to it— with addi- 
tional doses of the organism. Over a period of time, the animal's blood 
built up massive amounts of antibody to the pathogen. This process 
rendered the animal "hyperimmune" and, potentially, made its serum 
valuable as a treatment against an active case of the disease. 

By the spring of 1908, Ricketts had produced an antiserum that 
protected guinea pigs against spotted fever if given a short time after 
infection. It was impossible, of course, to judge whether it would have 
any effect on humans, especially since it would have to be given in 
relatively large amounts. Moreover, information about anaphylaxis — 
the life-threatening allergic response that struck some people injected 
more than once with the foreign proteins in horse serum— was just 
becoming widely known. Writing to Thomas D. Tuttle, Ricketts noted 
a recently published article in the Journal of the American Medical 
Association dealing with anaphylaxis, but he expressed the opinion 
that large doses of his antiserum would carry no significant risk. "I 
have known over 1000 cc of horse serum, in the shape of tetanus 
antitoxin, to be given subcutaneously, intravenously, and subdurally, 
without producing any serious damage. "^^ 

Because of the high mortality from spotted fever in the Bitterroot 
Valley, Ricketts concluded that it would do no harm to test the serum 
on victims of the disease. During the spring of 1908 he administered 
the serum to nine spotted fever patients. Six of them, all extremely ill, 
died in spite of the treatment. In each of the three recoveries, there 
were circumstances that threw doubt on the efficacy of the serum. The 
disease was exceptionally mild from the beginning in a seven-year-old 
boy, who received 138 cc of the serum, and in one adult male, whose 
physician failed to keep records on the amount of serum administered. 
In the case of the child, moreover, it was widely known that children 
were more likely to recover than adults. A more typical case treated 
that spring occurred in an adult male, who received 120 cc of the 
serum over three days. Although the man lived, his recovery took two 
weeks. Ricketts doubted that the serum caused the recovery, observing 
that "there would be less difficulty in recognizing a curative effect of 
the serum if its injection were followed by a sudden subsidence of 



68 



Rocky Mountain Spotted Fever 



symptoms, such as antitoxin causes in diphtheria. "^^ 

In contrast to Ricketts's own conclusions, the local press judged that 
the serum had indeed saved the victims' lives. It was hardly surprising 
that the relatives of spotted fever patients grasped at the promise of 
the serum and rarely worried about its proven efficacy. Because of this, 
Ricketts received numerous appeals in the spring of 1909 for additional 
quantities of his serum. Financial constraints had prevented him from 
producing additional batches, but he sent what he had on hand, even 
though it was old and had probably lost, in his estimate, 20 percent 
of its curative value. Since the efficacy of the serum had not been 
disproved, Ricketts was reluctant to deny it to those who sought it. 
"From the humanitarian standpoint," he wrote to Tuttle, "it seems 
that the serum should be supplied until it has been shown to be worth 
something or nothing." Ricketts also noted that his student Paul G. 
Heinemann was attempting to concentrate the serum as was done with 
diphtheria antitoxin to make it more effective. 

All of these lines of research were suspended or slowed down in 
1909 because of one insurmountable obstacle: money. In 1907 the 
Montana state legislature had appropriated two thousand dollars for 
Ricketts's work, but it was completely used up during that year. In 
1908 Missoula and Ravalli counties appropriated five hundred dollars 
each, and the state board of health contributed five hundred dollars, 
a total of fifteen hundred dollars that was also rapidly consumed. 
Ricketts and Tuttle also appealed to Idaho authorities for financial 
support, noting that spotted fever afflicted their citizens as well. It was 
a futile request. Idaho apparently felt no obligation to appropriate 
funds for what was perceived as Montana's unique problem. 

In March 1909 the Montana state legislature committed itself to 
continuing Ricketts's work through a special bill appropriating six 
thousand dollars for two years' investigations. Ricketts was gratified, 
observing to Tuttle that it was "quite a remarkable thing for a state 
legislature to fall in with the plans of the State Board of Health so 
harmoniously in the interests of public health. "^^ Unfortunately, the 
state legislature had voted to expend more monies than would be 
collected in revenues. Since the Montana state constitution required a 
balanced budget, the task of reconciling revenues with outlays was 
given to the State Board of Examiners, the body appointed to oversee 
the state's finances. In order to assure funding of the essential state 
projects, authorized by public bills, the examiners suspended appro- 
priations for all special bills enacted in 1909 until revenue was increased 
to cover them. Funds for the spotted fever investigations were not the 



Dr. Rtcketts's Discoveries 



69 



only ones withheld; those for the state agricultural experiment station, 
for example, were similarly impounded/ ° 

The examiners' decision came just before the 1909 tick season in 
the Bitterroot Valley. Miles Romney, proprietor of the Western News, 
informed Tuttle about an early spotted fever death that spring and 
pleaded with the state board of health, "in the interest of common 
humanity," to allow Ricketts's work to proceed. No large local sub- 
scription drive or appropriation, however, was undertaken to replace 
the impounded state money. To demonstrate appreciation for Ricketts's 
work, the University of Montana, at the urging of the Montana Medical 
Association, conferred on him an honorary degree at its 1909 com- 
mencement.'^ 

Although no one was able to budge the State Board of Examiners 
from its fiscal decision, members of the state board of health suggested 
to Ricketts that if he could obtain funds from a private source, such 
as the university or the associated John Rockefeller McCormick Me- 
morial Institute for Infectious Diseases, the funds would eventually be 
released and the state would pay him back."^ For those institutions, 
however, the probability that Montana would raise the needed reve- 
nues was too uncertain to convince them that this would be a wise 
course of action. Ricketts's spotted fever work had earned him a gold 
medal from the American Medical Association as well as several offers 
of professorships from universities, and it was difficult for the rising 
research star to stop productive investigations until money again be- 
came available. 

During the summer of 1909, Ludvig Hektoen urged Ricketts to 
consider working on tabardillo, the Mexican typhus fever named for 
the rash that resembled a red cloak on its victims. This disease, Hektoen 
noted, had many characteristics in common with spotted fever, and 
neither its cause nor its means of transmission was known. Later noting 
that he would have decUned or postponed his work on typhus had he 
"known surely that . . . [Montana authorities] would come up with 
the money," Ricketts decided that he must go forward in some line 
of research. Hektoen arranged for the Mexican government, the Uni- 
versity of Chicago, and the Memorial Institute to share the financing 
of the project. Since the annual epidemics of tabardillo usually started 
in late autumn, Ricketts left for Mexico City in December 1909.^'* 

Only after arriving in Mexico did Ricketts learn that a French re- 
searcher, Charles Nicolle, working in Tunis, Africa, had recently dem- 
onstrated the body louse as the vector of typhus. In addition. Hygienic 
Laboratory researchers John F. Anderson, who had investigated spot- 



70 



Rocky Mountain Spotted Fever 



ted fever in 1903, and Joseph Goldberger, who suffered a bout with 
typhus while studying it, had confirmed Nicolle's findings and suc- 
ceeded in directly inoculating the typhus pathogen into monkeys. 
Gamely proceeding with his work even though he had lost the chance 
to claim priority, Ricketts and his student Russell M. Wilder also 
confirmed these findings. More importantly, they described an orga- 
nism similar to the spotted fever organism that was consistently found 
in the blood of patients, in the lice that fed on these patients, and in 
the feces of the infected lice.^^ 

Shortly after the new year, Thomas D. Tuttle, secretary of the Mon- 
tana State Board of Health, received word that the State Board of 
Examiners had released the funds for spotted fever work. A relieved 
Ricketts, who had recently accepted a professorship at the University 
of Pennsylvania and was preparing to leave Chicago, wrote Tuttle that 
he hoped the 19 10 work — a "pretty heavy piece of work" on "the 
role of the small wild animals"— would conclude his spotted fever 
investigations. Ricketts projected that he would be able to leave Mexico 
City by 20 April and would be in Montana in mid May. Tuttle, however, 
urged him to come even sooner, assuring him that the state would 
fund all necessary expenses, including the salaries of his assistants. 
"Employ such men as you need," Tuttle wrote, but "for goodness' 
sake get them out as soon as possible, as the weather is getting very 
warm and the ticks are coming out."^^ 

From his lodgings at the American Club in Mexico City, Ricketts 
wrote to his student Josiah J. Moore, instructing him to proceed to 
Montana, but Ricketts himself continued to work on tabardillo. The 
work was dangerous, for the tiny lice that had been implicated as the 
vectors of the disease were often difficult to detect. Ricketts avoided 
the hospital in which typhus patients were treated. The medical staff, 
he observed, were "very filthy in the care of their patients," and living 
Hce could be found in the bed linens of victims "almost any day." 
Except for comments to trusted scientific colleagues, Ricketts said little 
of the peril in which he worked. "Mrs. Ricketts is more or less worried 
now," he confided to one friend, "and if she should learn about . . . 
[the hospital conditions], I think I should have to go home in order 
to quiet her fears. "^^ 

In mid April, Ricketts did become infected with typhus. Russell M. 
Wilder communicated this unfortunate turn of events to Tuttle but 
added optimistically, "I have every reason to believe that Dr. Ricketts 
will make a safe recovery from his illness." Ricketts was only thirty- 
nine and, like Goldberger before him, should probably have been able 
to fight off the disease. Throughout the fall of 1909, however, Ricketts 



Dr. Ricketts's Discoveries 



71 



referred to an unnamed illness that periodically plagued him and pos- 
sibly lowered his resistance. On 3 May 19 10 he succumbed to typhus 
in Mexico. In Montana the news was grimly received. "In the midst 
of his experiments," said the Daily Missoulian, "the man, beloved in 
Montana and honored in the world of learning, was stricken by the 
very ailment for which he sought a remedy.""^ 

Ricketts's death brought spotted fever investigations to an abrupt 
halt. Tuttle wired Josiah J. Moore, who had already arrived in the 
Bitterroot and established a camp, to make up a statement of expenses 
and return to Chicago. Since the Montana state legislature had ap- 
propriated funds specifically for Ricketts's use, not even Moore — a 
Montana native of "exceptionable abihty" who had worked with 
Ricketts for three years on spotted fever— was authorized to carry on 
the investigations.^^ A few experiments already underway were pub- 
hshed, many in a memorial volume prepared by Ricketts's colleagues 
and students. Tuttle corresponded in vain with several of Ricketts's 
associates, hoping that they might continue the work.^^ Without the 
leadership of the dynamic Ricketts, however, laboratory experimen- 
tation on spotted fever virtually ceased. 

In the short space of three years, Howard Taylor Ricketts had re- 
directed scientific thinking about Rocky Mountain spotted fever. Mov- 
ing beyond the dogma surrounding arthropod transmission of disease, 
he demonstrated that spotted fever was indeed tick borne and that 
infected ticks existed in nature. His studies of the tick produced a plan 
for controlling the pests and their mammalian hosts. With relentless 
persistence, he pursued techniques for producing a vaccine and anti- 
serum against the disease. Trusting his experimental observations, 
Ricketts refused to be discouraged by his inability to culture the spotted 
fever organism in accordance with Koch's postulates. Although his 
untimely death cut short further work, each line of research was pro- 
ductively followed by his successors in spotted fever work. Ricketts's 
contributions were recognized by his scientific peers when the group 
of diseases to which spotted fever and typhus belong was named 
rickettsial in his honor. For the people of the Bitterroot Valley, his 
expertise and imagination provided not only a hope, unfulfilled, for 
an effective antiserum, but also a focus, the tick, for efforts against 
the dread disease. 



Chapter Five 



Tick Eradication Efforts, 

IpII-I^lO 

When the devil made the tick, he overlooked a bet in not giving it wings. 

Bitterroot Valley rancher, 19 19 



If the first decade of spotted fever research in the Bitterroot Valley 
belonged to bacteriologists, the second decade clearly was dominated 
by entomological control methods. Since no effective medical preven- 
tive or therapy had been developed for spotted fever, an attack on the 
tick itself seemed the only immediate hope of ridding the valley of its 
scourge. Texas cattle fever was being controlled in the southern states 
with a rigorous vector control program, Major William Crawford 
Gorgas of the U.S. Army had dramatically demonstrated in Havana 
that yellow fever could be halted with mosquito control methods, and 
the U.S. Public Health and Marine Hospital Service had suppressed 
bubonic plague epidemics in San Francisco and New Orleans by at- 
tacking fleas and their host rats. These successful campaigns inspired 
hope that spotted fever could be eliminated in a similar manner. 

It was not until the late nineteenth century that ticks were identified 
as carriers of pathogenic microorganisms, but they had been recognized 
as unwelcome parasites at least as early as 550 B.C., when Homer 
described the sufferings of an infested dog. The misery-causing po- 
tential of ticks was somewhat offset by allegedly therapeutic quaHties 
for which they were valued. In ancient Chinese medicine white cattle 
ticks were ground with rice powder, formed into cakes, and admin- 
istered to children as a preventive for smallpox. Galen and other 
authorities of late antiquity, whose medical opinions continued to 
dominate the thought of the Middle Ages, recommended the crushed 
bodies of ticks for a variety of medical problems. Used as a paste or 
taken in wine, ticks were employed as aphrodisiacs and used to clean 
ulcerations, to arrest menstruation, to prevent the regrowth of un- 
wanted hair, and to treat anal fistula.^ 



72 





Ticks waiting on vegetation 
for a host to pass by. 
(Courtesy of the Rocky 
Mountain Laboratories, 
MAID.) 



From the Renaissance until the nineteenth century, ticks were rarely 
mentioned in medical treatises. By the time Theobald Smith and Fred 
L. Kilbourne discovered that the cattle tick transmitted a pathogenic 
protozoan organism, however, zoology had become a flourishing en- 
terprise in universities, hence much was already known about ticks 
themselves. In zoological classification schemes ticks resided in the 
phylum Arthropoda, comprised of creatures having segmented bodies 
with paired jointed appendages and an exoskeleton. Containing more 
species than all other phyla combined, the arthropods encompassed 
insects, centipedes, crabs, lobsters, mites, and scorpions as well as 
ticks. Ticks, mites, and scorpions— arthropods having eight legs, no 
wings or antennae, simple eyes, if any, and a fused head and thorax— 
were further subdivided into the class Arachnida. Within this class, 
the order Acarina included ticks and mites but excluded scorpions. 
Ticks alone were placed into the superfamily Ixodoidea, which con- 
tained two families, the Argasidae and the Ixodidae. These were com- 
monly known as soft ticks and hard ticks, respectively, because the 
latter possessed a shield or scutum that partially covered their backs. 



74 



Rocky Mountain Spotted Fever 



Among the hard ticks, the Dermacentor genus was widespread in the 
United States and contained many species.^ 

When first suspected of transmitting Rocky Mountain spotted fever, 
ticks were generally described in nonspecific terms. In their initial 1902 
report, Louis B. Wilson and William M. Chowning spoke of spotted 
fever as a disease carried by "a tick."^ They sent specimens to zoologist 
Charles Wardell Stiles at the Hygienic Laboratory of the U.S. PubHc 
Health and Marine Hospital Service in Washington, D.C., for his expert 
determination, as did John F. Anderson the following year. Possibly 
influenced by Wilson and Chowning's claim that a Piroplasma was 
the cause of spotted fever. Stiles provisionally determined that the tick 
was Dermacentor reticulatus, the same tick that transmitted a piro- 
plasmic disease to dogs. The zoologist stipulated, however, that further 
study was necessary for a definite determination because of certain 
differences he had observed between the Rocky Mountain wood tick 
and D. reticulatus.'^ When Stiles published the report of his own in- 
vestigation into spotted fever, he called the tick Dermacentor ander- 
soni. This new name, by which he honored his colleague John F. 
Anderson, implied that the tick was a separate species. Stiles mentioned 
the name only once, however, and he provided no description of 
uniqueness. Both Walter W. King and Howard Taylor Ricketts called 
the tick used in their transmission experiments Dermacentor occiden- 
talism which was actually a common California tick. Ricketts continued 
to use this name until 1909.^ 

In June 1908, Nathan Banks, a specialist on ticks with the U.S. 
Bureau of Entomology, seemed to resolve the confusing nomenclature 
when he published "A Revision of the Ixodoidea, or Ticks, of the 
United States," describing and defining the Rocky Mountain wood 
tick as Dermacentor venustus (Banks). ^ Less than a month later, how- 
ever. Stiles refuted Banks's claim, maintaining that D. venustus was a 
Texas tick with different characteristics and that his 1905 designation, 
D. andersoni (Stiles), should be retained. In August 1910, Stiles pub- 
lished a detailed scientific study on the value of microscopic structural 
differences in choosing names for Dermacentor ticks. This new re- 
search. Stiles argued, proved his designation D. andersoni beyond 
doubt. Banks, in contrast, continued to support his claim that D. 
venustus was the identical tick and that his 1908 published description 
estabhshed priority.^ 

After 19 10 the inconclusive war of names stalemated. Entomologists 
continued to call the tick D. venustus^ and physicians from Stiles's 
agency, the U.S. Public Health and Marine Hospital Service, always 
referred to D. andersoni. Reports from the two groups appeared side 



Tick Eradication Efforts, ipii-ipio 



75 



by side in official Montana publications, utilizing the two different 
names without explanation or apology to the lay reader, who must 
have been somewhat confused if not familiar with the controversy.^ 
In 1923 the question was submitted to the International Commission 
on Zoological Nomenclature, an official body created to resolve such 
disputes. Although a member, Stiles did not vote because of his personal 
involvement in the case. DecHning to judge which tick carried the 
disease, the commission took a narrow approach to the types of speci- 
mens represented by Stiles's and Banks's names. The majority opinion 
declared that Dermacentor venustus belonged to a form with a Texas 
tick as a holotype and that Dermacentor andersoni belonged to a form 
with a tick from Woodman, Montana, as the holotype. Since spotted 
fever was unknown in Texas at that time, D. andersoni became the 
official name for the spotted fever tick.^ 

This taxonomic tempest embodied on a superficial level a deeper 
internecine rivalry between physicians and entomologists. Before the 
link between arthropods and disease had been established, each group's 
areas of expertise seemed clearly defined: physicians treated sick peo- 
ple; entomologists primarily assisted farmers in eliminating crop-de- 
stroying insects. A relatively new professional group, entomologists 
were still struggling to establish a separate identity from zoology, their 
older and broader parent disciphne.^° 

During the earliest period of white settlement of North America, 
there had been no need for such specially trained scientists because 
indigenous insects rarely caused problems for farmers. After the Amer- 
ican Revolution, however, the gradual normalization of trade led to 
the importation of foreign plants, some of which harbored injurious 
insects that multiplied rapidly. Individual states began to employ en- 
tomologists during the 1840s, and in 1854 the U.S. Patent Office 
employed a person to collect statistics on seeds, fruits, and insects. 
Specialists in entomology were few and the literature sparse throughout 
the 1 8 60s, even though the 1862 act establishing the Department of 
Agriculture boosted the status of entomologists by authorizing their 
employment to provide useful information for farmers. The 1874-76 
flight of locusts from Montana and the Dakotas as far south as Missouri 
focused additional attention on the devastation that insects could cause 
and led to the formation of a federal entomological commission to 
study the depredations of the locusts. In 1887, partly as a result of 
the commission's reports. Congress authorized the establishment of 
agricultural experiment stations that included speciaHsts in entomol- 
ogy.'' 

The development of graduate programs in universities and the es- 



76 



Rocky Mountain Spotted Fever 



tablishment of professional societies, such as the Association of Eco- 
nomic Entomologists, founded in 1889, also advanced entomology as 
a profession. Post-Civil War industrialization and urbanization en- 
hanced this trend, altering traditional cultural patterns and fostering 
the development of expert knov^^ledge in a variety of fields. The term 
medical entomology was coined in 1909 for the specific study of ar- 
thropods and disease, but actual professional differentiation remained 
far from rigid. Zoologists interested in all forms of parasitism studied 
arthropods as well as worms, bacteria, and protozoa. With the dis- 
coveries in the 1890s that arthropods could transmit pathogenic mi- 
croorganisms to animals and humans, veterinarians, physicians, and 
public health researchers also became interested in the field. As these 
groups pursued overlapping goals, professional rivalries often marred 
the more altruistic aim of selfless devotion to the advancement of 
science. 

Physicians, who had a much longer professional history than most 
other groups and whose status was rising with each new bacteriological 
triumph, were often accused of ignoring or subordinating the contri- 
butions of other professions.^^ For human diseases, physicians coun- 
tered such criticism with the observation that they alone were properly 
trained to apply speciaHzed knowledge to a pubHc health problem. 
Because Rocky Mountain spotted fever was transmitted by ticks, both 
physicians and entomologists were interested in its control. Unfortu- 
nately, a bitter power struggle developed between the two groups in 
Montana that reverberated to the federal level and retarded coordi- 
nation of the effort. 

Initially this struggle centered on two strong-willed men, Thomas 
D. Tuttle, secretary of the Montana State Board of Health, and Robert 
A. Cooley, the Montana state entomologist. Tuttle, who had fought 
for increased funding for pubhc health and had vigorously enforced 
local health ordinances, assumed after the death of Howard Taylor 
Ricketts that the Montana State Board of Health would continue to 
direct the attack on Rocky Mountain spotted fever. In March 19 11 
he appealed to Surgeon General Walter Wyman of the U.S. Pubhc 
Health and Marine Hospital Service to send a new researcher who 
could utilize state funds appropriated for spotted fever research. Wy- 
man stalled, citing the heavy demands on Service officers. After con- 
tinued appeals from Tuttle and Montana Senators Paris Gibson and 
Henry L. Myers, however, Wyman relented and in mid May detailed 
Passed Assistant Surgeon Thomas B. McClintic to Montana. 

A thirty-eight-year-old graduate of the University of Virginia Med- 
ical School and twelve-year veteran Service officer, McClintic had 



Tick Eradication Efforts, i^ii-ipzo 



77 



considerable experience in quarantine work, both in the United States 
and abroad, including "the usual tour of duty of officers in the tropics." 
During several periods when he was stationed at the Hygienic Lab- 
oratory, McChntic had been found to have a "special fitness for re- 
search work," and it was the combination of field experience and 
laboratory expertise that induced Wyman to select him as the officer 
who would tackle the mysterious spotted fever. During the summer 
of 191 1, McClintic hoped to demonstrate the practicabiHty of pre- 
venting spotted fever in the limited area around Victor, Montana, 
using tick control principles outlined by Ricketts.^^ 

On his way to the Bitterroot, McClintic stopped in Bozeman, Mon- 
tana, to consult with Cooley, the state entomologist, who had been 
researching the life cycle and habits of the tick. To his surprise, 
McClintic found that Cooley had already raised a subscription to 
construct an experimental dipping vat for tick control in the Florence 
area, about fifteen miles north of Victor. This project, Cooley noted, 
was actually funded and staffed by representatives of the U.S. Bureau 
of Entomology and the U.S. Bureau of Biological Survey. When 
McClintic and Tuttle arrived in Florence three days later to assess the 
situation, they were utterly astonished to discover Cooley in the field, 
supervising the project himself. 

Having known nothing about the experimental dipping vat and, 
perhaps more importantly, having expended great effort to persuade 
the U.S. Public Health and Marine Hospital Service to resume spotted 
fever work, Tuttle experienced embarrassment that rapidly turned to 
fury. It appeared clear to him that the entomologists were meddling 
in a public health matter. Tuttle and other members of the Montana 
State Board of Health immediately undertook efforts to force the 
perceived interlopers out of spotted fever work, but Cooley proved as 
adamant as Tuttle, and the hostility between the two men intensified. 

Robert A. Cooley, the focus of Tuttle's concern, was born on 27 
June 1873 Deerfield, Massachusetts. After receiving a B.S. degree 
in 1895 ^^om Massachusetts Agricultural College, Cooley completed 
four additional years of graduate work in the pioneer entomological 
graduate school of that institution.^^ Before fulfilling all the require- 
ments for his Ph.D., however, he accepted a position as professor of 
zoology and entomology at the Montana State College in Bozeman. 
Since the college housed the state agricultural experiment station, Coo- 
ley also assumed duties as the station entomologist. In 1903 he helped 
write legislation that conferred upon the agricultural station ento- 
mologist the additional title of Montana state entomologist. A man 
who inspired intense loyalty in his friends and students, Cooley, Hke 



78 



Rocky Mountain Spotted Fever 



Robert A. Cooley, secretary 
of the Montana State Board 
of Entomology, championed 
Hvestock dipping to eUminate 
the spotted fever tick from the 
Bitterroot Valley. He hoped to 
repeat the success of southern 
entomologists who had con- 
trolled Texas cattle fever, an- 
other tick-borne disease, by 
this method. (Courtesy of the 
Rocky Mountain Laborato- 
ries, NIAID.) 

Tuttle, had a stubborn streak that made him unwilling to compromise 
when facing someone he perceived as an adversary. 

Cooley first entered spotted fever work as a result of Ricketts's 
recommendation that the Montana State Board of Health locate an 
entomologist to launch long-range, year-round studies of the spotted 
fever tick. Having no idea that conflict lay ahead, Tuttle logically sought 
assistance from the state entomologist. In 1908, Cooley and his student 
Willard V. King began to study Montana ticks in a noninfected area 
near Bozeman and formulated plans to repeat Ricketts's work on the 
tick's life cycle. Ricketts, who was not entirely pleased that Cooley 
chose to repeat these experiments, commented to Tuttle that Cooley 
seemed little inclined "to concede that the direction of his work should 
be guided by my results and conclusions." Cooley's efforts to raise a 
separate fund from Missoula and RavaUi counties for entomological 
work on spotted fever, Ricketts continued, also suggested that Cooley 
"was inclined to carry on his work independently." Tuttle had found 
Cooley unwilling to allow the report on his 1908 work to be incor- 
porated in the state board of health's biennial report. Cooley preferred 
to publish it with his own report as state entomologist since the work 
had been done with funds from that office. 

During the winter of 1908-9, Cooley traveled to Washington, D.C., 
and consulted with representatives of the U.S. Bureau of Entomology, 




Tick Eradication Efforts, i^ii-i^zo 



79 



who had already sponsored a tick survey of the northwest states in 
which Willard V. King had participated. Since the range of the Rocky 
Mountain wood tick was found to extend from the northern edge of 
New Mexico to Canada and from CaHfornia's Cascade range to the 
western Great Plains, plans were laid for a collaborative study between 
the U.S. Bureau of Entomology and the U.S. Bureau of Biological 
Survey, the federal agency charged with wildlife surveys and control 
of animal pests, to investigate further the hosts and habits of the disease- 
bearing tick.^° During the spring of 19 lo, while the Montana State 
Board of Health awaited Ricketts's arrival only to be devastated by 
news of his death, Cooley established a field station in the Bitterroot 
Valley on Sweeney Creek, southwest of Florence, an area known to 
be infected with spotted fever. Calling the station Camp Venustus after 
Nathan Banks's designation of the spotted fever tick, Cooley assembled 
three representatives from federal agencies to conduct the study: Wil- 
lard V. King from the U.S. Bureau of Entomology and Arthur H. Howell 
and Clarence Birdseye from the U.S. Bureau of Biological Survey. 
Birdseye, who later developed a technique for freezing foods and 
launched the company that bears his name, was embarking on his first 
practical research as a young college graduate. Howell, the group's 
senior member, returned east after a short time. Purportedly, King and 
Birdseye, seeking first-author privileges on the publications that were 
expected to result, employed an elaborate practical joke to scare Howell 
into believing that he had been bitten by a potentially infected tick.^^ 
In order to protect themselves, King and Birdseye developed a num- 
ber of methods that became standard procedure for field studies of 
spotted fever. They wore high-topped shoes to which were attached 
pieces of khaki cloth fastened by drawstrings higher up on the leg. To 
their cotton outer garments, they applied kerosene as a tick repellent, 
a measure that seemed to be useful, at least until the kerosene evap- 
orated. At night they fumigated their clothing in an airtight closet with 
bisulphide of carbon. On the basis of Josiah J. Moore's research that 
an infected tick had to feed for nearly two hours in order to transmit 
spotted fever, the men regularly conducted rigorous examinations of 
their bodies within that time period. This regimen proved successful: 
although occasional bites occurred, neither of them contracted spotted 
fever. 

King and Birdseye sought to determine more precisely the life cycle 
of the tick and to identify its hosts in each stage. Using a white woolen 
or flannel cloth attached to a pole hke a flag, King collected ticks from 
brush. Birdseye shot and trapped 717 small wild animals— thereby 
incurring the wrath of the game warden— and collected 4,495 addi- 



8o 



Rocky Mountain Spotted Fever 




Flagging for ticks in the Bitterroot Valley. The flannel flags, dragged across 
brush vegetation favored by ticks, were used to obtain ticks for entomolog- 
ical studies and for spotted fever vaccine production. The collector pro- 
tected himself by tucking his pants into his boots, by w^earing long-sleeved 
clothing, and by inspecting his body at regular intervals. (Courtesy of the 
Rocky Mountain Laboratories, NIAID.) 



tional ticks/^ Samples of different species were sent to the Dallas, 
Texas, station of the U.S. Bureau of Entomology to be reared and 
identified. King's studies established that the spotted fever tick did not 
complete its Hfe cycle in one year, as Ricketts believed, but instead 
had at least a two-year life cycle, spending the winter either as an adult 
or as a nymph. Birdseye determined that the immature stages of the 
tick fed on a variety of small animals while the adult ticks fed exclu- 
sively on large animals such as horses, cows, sheep, and goats. When 
he assessed these findings, Cooley concluded that the spotted fever tick 
might be eliminated Hke the Texas cattle fever tick— by preventing 
adults from reaching a host on which to feed and breed. Birdseye's 
observation that adult ticks fed only on large animals, moreover, sug- 
gested that destroying the small rodents that served as hosts to the 



Tick Eradication Efforts, ipii-ipio 



8i 



larval and nymphal tick stages might be completely unnecessary.^"^ 

As this work was being completed, Tuttle was preparing the biennial 
report of the state board of health. Perhaps wishing to include some 
positive note on progress in spotted fever research to lessen the impact 
of Ricketts's death, Tuttle again invited Cooley to incorporate a full 
or summary report of the entomological work, or, at a minimum, a 
mention that cooperative work was taking place. On the advice of 
W. D. Hunter of the U.S. Bureau of Entomology, however, Cooley 
again chose to pubhsh his findings separately.^^' 

During the fall and winter of 19 lo, Cooley sought funds to imple- 
ment a tick control program from Governor Edwin L. Norris and from 
W. E. McMurry, Ravalli County's representative to the Montana state 
legislature. Cooley asserted that the execution of his plan was "purely 
an Entomological matter" and asked for ten thousand dollars over 
two years either for the use of the state entomologist or for the state 
board of health with the specification that the money was for tick 
eradication under the direction of the state entomologist. Although 
neither state official seemed inclined to support this request, Cooley 
intimated to several people that Tuttle might be persuaded to turn over 
all or a portion of the two-thousand-dollar state board of health ap- 
propriation to him for tick eradication work. After the incident with 
McClintic, however, Tuttle would scarcely have allocated Cooley a 
dime.^^ 

With no state money available, Cooley's 19 11 program went for- 
ward under continued funding from the U.S. Bureaus of Entomology 
and Biological Survey. Stationed at an abandoned saloon in Florence, 
King conducted experiments to determine how long ticks could survive 
without feeding, and Birdseye, who maintained that rodent destruction 
was indeed necessary, developed an improved formula of poisoned 
rolled oats.^^ In King's longevity experiments, conducted outside Flor- 
ence at the same cabin on Sweeney Creek used the year before, ticks 
were placed in tubes in the ground. A plug of earth in the bottom 
prevented their escape but ensured contact with ground moisture. 
Although a "man and animal proof fence" was built and a caretaker 
hired, the experiment was judged by Tuttle to constitute a menace to 
the surrounding citizenry, and Cooley, on the advice of his superior 
at the college, reluctantly removed them.^^ 

In May 19 11, just before McClintic arrived in the Bitterroot, Cooley 
published an outhne for control of spotted fever based primarily on 
the 19 10 investigations. His principal recommendation appeared in 
boldface type: "The key to the situation seems to be the destruction 
of ticks on domestic animals only." Montana newspapers did not miss 



82 



Rocky Mountain Spotted Fever 



the implication of this statement, and the headUne of one paper pro- 
claimed, "Cooley Sounds the Key Note to Spotted Fever Eradication."^^ 

For Tuttle the cumulative effects of Cooley's actions inspired outrage. 
The new^spaper headlines indicated that Cooley w^as arrogating to 
himself the program outlined in 1908 by Ricketts, whom Tuttle ad- 
mired greatly. Cooley's longevity experiments imphed disregard for 
pubHc safety. When these offenses v^ere added to Cooley's persistent 
attempts to establish and fund a separate entomological program for 
spotted fever eradication— not to mention the embarrassment over the 
incident when McClintic arrived— Tuttle and his colleagues on the 
state board of health determined that strong action was necessary. At 
its meeting on 5 June, the state board passed a resolution asking 
Cooley's employer, the state board of education, to instruct the en- 
tomologist that he should cooperate with the work of the state board 
of health already in progress. ^° 

Apparently nothing came of this request and the situation escalated, 
for Tuttle called a special meeting of the board of health 24 July. He 
read a prepared statement outlining in detail Cooley's high crimes and 
misdemeanors. In addition to the other charges, Tuttle noted that in 
19 10, Cooley had conducted experiments in his laboratory at Montana 
State College with spotted fever-infected ticks. The four guinea pigs 
used in the investigation had died, but Cooley had not suspected spotted 
fever because their temperatures had not risen precipitously. Only when 
he examined the body of the last dead guinea pig did Cooley notice 
a rash and the characteristic hemorrhagic scrotum. Tuttle cited this 
incident as a dangerous venture into work that should have been done 
only by a physician. "Playing with dynamite on a platform where there 
are fireworks being discharged is a mild experiment compared with 
that of working with infected ticks in a school or college by one who 
is not able to detect such a fatal disease as spotted fever." The board, 
already incensed, resolved to raise the matter more strongly with the 
state board of education. "We must uphold Dr. McClintic in every 
way," asserted the board president, William Treacy, "and if necessary 
fire this man Cooley."^^ 

The battle between Cooley and Tuttle, which was peppered with 
rumors of wildly intemperate remarks by both men, spilled over to 
the federal level when the Montana State Board of Health appealed 
to the U.S. Public Health and Marine Hospital Service and Cooley 
appealed to the U.S. Bureau of Entomology to clarify jurisdiction in 
spotted fever work. L. O. Howard, chief of the U.S. Bureau of En- 
tomology, contacted Surgeon General Walter Wyman, but to no avail. 
Commenting to Cooley that he had run "up against a stone wall," 



Tick Eradication Efforts, ipii-i^zo 



83 




Buildings in Victor, Montana, used as a laboratory by Thomas B. McClintic 
and Lunsford D. Fricks of the U.S. Public Health Service from 
(Courtesy of the Rocky Mountain Laboratories, NIAID.) 

Howard observ^ed that the U.S. Public Health and Marine Hospital 
Service saw "no necessity for any cooperation whatever" and appar- 
ently felt "perfectly competent to handle the whole matter."^^ Having 
successfully employed insect and rodent control measures to suppress 
other arthropod-borne diseases, the Service doubtless believed that its 
officers had sufficient expertise to oversee the dipping of livestock and 
the destruction of small rodents in Montana. Moreover, since all of- 
ficers were physicians, they could also employ bacteriological tech- 
niques in the study of the disease organism itself and offer medical 
assistance to the victims of spotted fever. As a result of this federal- 
level interchange, the U.S. Bureau of Entomology withdrew its support 
from Cooley's work at the end of the 19 11 season. The animosity- 
generated by the episode, however, remained. 

While this political storm raged around him, Thomas B. McCHntic 
initiated his own spotted fever research. Using funds appropriated by 
the Montana state legislature, McClintic hoped to test the feasibility 
of eradicating the tick in infected territories, to continue Ricketts's 
w^ork of testing the susceptibilit)- of the wild mammals to experimental 
inoculation with spotted fever, and to search for the infection among 
the wild mammals in nature. McClintic worked in a heavily infected 



84 



Rocky Mountain Spotted Fever 



district near Victor bounded on the north by Sweathouse Creek and 
on the south by Bear Creek. This was the territory in which Ricketts 
had found infected ticks in nature, and which, because of the presence 
of the disease, had become almost depopulated.^^ 

Because McClintic did not arrive until the latter part of May, it was 
quite late in the season to begin the work. Nonetheless, he determined 
to proceed, hoping to continue the work on a broader scale the fol- 
lowing year. In his plan for tick eradication, McClintic rejected the 
idea that dipping alone would accomplish tick eradication in the Bit- 
terroot, because, he said, "both in point of numbers and variety of 
species the fauna of the valley is excelled by very few other localities 
of similar size in the United States, and most of the mammals, both 
wild and domestic, harbor the tick in one form or another."^"^ 

McClintic oversaw construction of a $520 concrete vat for dipping 
livestock, which was made according to plans published by the De- 
partment of Agriculture and was similar to the vat used in Florence 
by the U.S. Bureau of Entomology. Nine feet deep, about five feet wide, 
and thirty-eight feet long at the water line, it was filled with approx- 
imately twenty-five hundred gallons of arsenical dipping fluid to a 
depth of five and one-half feet. This sufficed to immerse all stock, 
except for exceptionally large horses. Arriving at the vat, stock were 
herded into a corral and then driven individually up a ramp and onto 
a boiler-metal slide that sloped downward into the vat itself. After 
immersion, the stock were dried in dripping pens before being returned 
to pasture. 

Because corralling and driving the stock into the vat could be dif- 
ficult, a seasoned stock handler was essential. During the farmers' busy 
season, moreover, yet another person was needed to bring stock in 
from the surrounding farms. Most stock owners cooperated, McClintic 
observed, but a few, "as is usually the case in undertakings in the 
interest of the public health," objected to having anything done that 
caused "any inconvenience or work." By the middle of June the vat 
was completed, and dipping began under the supervision of McClintic 
and his assistant William Colby Rucker, who had recently arrived. 
Initially, 116 horses, 199 cattle, and 108 sheep were dipped. Two 
weeks later, on 3 July, redipping was begun, but "as the stock . . . 
was found to be practically free from ticks," only 38 horses, 57 cattle, 
and 60 sheep were dipped again.^^ 

In addition to the dipping program and recommendations for clear- 
ing and cultivation of land, McCHntic and Rucker launched a campaign 
to destroy the wild mammals on which the immature stages of the 
tick fed. The pine squirrel, yellow-bellied chipmunk, wood rat, wood- 



Tick Eradication Efforts, ipii-ipzo 



8S 



chuck, weasel, and badger were all targeted in this program, but the 
local ground squirrel, Citellus columbianus, was believed to be by far 
the most significant pest in the valley. Of 3,465 animals shot or trapped 
during the 191 1 season, 3,233 were ground squirrels. An uncounted 
number of other animals were killed with poisoned oats or with carbon 
bisulphide placed in their burrows, a method employed successfully 
against ground squirrels in the Service's antiplague campaign in Cal- 
ifornia.^^ 

McClintic and Rucker concluded their work in early August and 
moved their laboratory studies back to the Hygienic Laboratory in 
Washington, D.C. With the 191 2 election approaching, they found 
politics as well as the weather heating up in the nation's capital. To 
the Democrats' delight, the spUt between President William Howard 
Taft and his predecessor Theodore Roosevelt was polarizing the Re- 
publican party. McChntic and Rucker's own agency was likewise em- 
broiled in a political battle. A bill was before Congress to expand the 
authority of the U.S. Pubhc Health and Marine Hospital Service, but 
another bill proposed to create a wholly separate department of public 
health. Surgeon General Wyman was busily promoting the Service's 
bill and maneuvering to thwart those who would challenge his agency's 
hegemony in the federal bureaucracy.^^ 

In November the sixty-three-year-old Wyman died suddenly. Having 
served as surgeon general for twenty years, he was the only leader 
many Service officers could remember. McClintic interrupted his re- 
search to accompany Wyman's body to Saint Louis for burial. Iron- 
ically, Wyman's death breathed new life into a scaled-down version 
of his Service reform legislation. By the time McClintic and Rucker 
left for Montana in the spring of 19 1 2, another bill was moving through 
Congress that proposed to shorten the name of the Service to the U.S. 
Public Health Service and to broaden its authority to conduct re- 
search. 

During the fall and winter of 1911-12, McClintic tested a number 
of drugs for their therapeutic properties against spotted fever. This 
work, which resulted in negative findings, will be examined more 
closely in chapter 10. The spring of 19 12 held great promise for 
McClintic, both personally and professionally. On 2 March he married 
Theresa Drexel, and the following day the couple left for Montana to 
combine a honeymoon in the Bitterroot Valley with spotted fever 
research.'^^ McClintic and Rucker continued the work begun in 191 1, 
dipping livestock and kiUing small mammals. Their laboratory ex- 
periments were designed to study the natural history of the disease, 
the important work Ricketts had planned before his death from typhus. 



86 



Rocky Mountain Spotted Fever 



The natural history experiments were tedious. Ground squirrels and 
most other small mammals showed no identifiable illness, hence an 
indirect method had to be employed. McClintic and Rucker would 
inoculate a wild animal with spotted fever, and after five days its blood 
was injected into a guinea pig. Another waiting period followed, during 
which the guinea pig was observed for symptoms of the disease. If it 
became ill, the original animal was judged to be susceptible to exper- 
imental inoculation with spotted fever. If the guinea pig remained well, 
a final test was made by inoculating it with virulent spotted fever 
blood. If the guinea pig again remained healthy, the experiment was 
inconclusive because it was judged to have been immune to spotted 
fever from the outset. If the guinea pig succumbed, however, the orig- 
inal mammal was declared to have acquired immunity from an earlier 
infection in nature. 

By this time-consuming method, McClintic determined that, in ad- 
dition to ground squirrels, weasels, woodchucks, and mountain goats 
were susceptible to the disease. Many other animals were tested with 
negative results. Badgers, for example, could be experimentally in- 
fected, but infection was slight and infrequent. Since the spotted fever 
tick had never been observed feeding on a badger, moreover, the animal 
could practically be eliminated as a potential reservoir in nature. 

Locating immune ground squirrels in nature was one key to iden- 
tifying them as a significant mammalian reservoir of the disease. During 
the 191 1 season, McClintic had experimented with 21 ground squirrels 
from the heavily infected Victor area, but the results were inconclusive. 
In 19 1 2 he expanded the experiments, using 194 ground squirrels. Of 
these, 34 again gave questionable results and had to be discarded. 
Among the 160 remaining ground squirrels, McClintic found 40 to 
be naturally immune. When the ground squirrels were grouped ac- 
cording to the locality from which they were collected, a higher per- 
centage of immune squirrels was found in highly infected spotted fever 
areas."^^ 

Another major line of research focused on a large-scale study of 
infective ticks in nature. McClintic collected nearly 2,000 ticks from 
different localities in the Bitterroot and from Bannock County, Idaho. 
His results were similar to those obtained by Ricketts, but, because 
of the large scale on which they had been conducted, they established 
more conclusively that infected ticks did indeed exist in nature. "^"^ 

Early in August, McClintic completed the season's work and pre- 
pared his laboratory experiments once more for transfer to the Hygienic 
Laboratory. On 9 August, however. Service headquarters in Washing- 
ton, D.C., received a wire from Thomas D. Turtle that McCHntic was 



Tick Eradication Efforts, ipii-ipzo 



87 



In 1911 and 1912 Thomas B. 
McClintic of the U.S. PubUc 
Health and Marine Hospital Ser- 
vice continued Howard Taylor 
Ricketts's studies of spotted fe- 
ver in nature, providing more 
conclusive proof of Ricketts's 
tentative results. Near the end 
of his work in 19 12, McClintic 
became infected with spotted 
fever and died— the first of 
many laboratory investigators 
who lost their lives in the study 
of the deadly disease. In 19 14 
the U.S. Congress recognized 
McClintic's death in the line of 
duty with a private act. (Cour- 
tesy of the National Library of 
Medicine.) 




ill with an undiagnosed disease but proceeding east by train, where 
he planned to join his wife, who had returned earlier. By the time the 
train reached Chicago, it was clear to Karl H. Kellogg, a Stevensville 
physician who accompanied McClintic, that the young investigator 
had fallen victim to spotted fever. Determined to return home, however, 
McClintic rebuffed an offer of medical care in Chicago. Before the 
train reached Baltimore, McClintic had lost consciousness, and he died 
at Georgetown University Hospital on 13 August 19 12, the evening 
of his arrival and the day before President Taft signed the act that 
shortened the Service's name to U.S. Public Health Service. In 19 14 
the U.S. Congress recognized McClintic's service and death in the line 
of duty in a private act. It provided a lump sum award of $5,760 — 
an amount equal to two years' pay and allowances— to Theresa Drexel 
McClintic, who never remarried. 

Spotted fever had claimed its first victim among the researchers who 
probed its mysteries. McClintic's death cast the dangers of research 
in bold relief, but according to a newspaper in Washington, D.C., there 
was no question that the work would be resumed. Rupert Blue, the 
new surgeon general of the renamed U.S. Public Health Service, chose 
Lunsford Dickson Pricks to replace McClintic in spotted fever work."^^ 
The son of a physician in Rising Fawn, Georgia, Pricks was born on 



88 



Rocky Mountain Spotted Fever 



From 1913 to 191 7, Lunsford D. 
Fricks supervised the U.S. Public 
Health Service program to rid 
the Bitterroot Valley of spotted 
fever. His proposals clashed with 
those supported by the Montana 
State Board of Entomology. 
(Courtesy of the National 
Library of Medicine.) 




18 July 1873. After graduating first in the 1897 class of the Chatta- 
nooga (Tennessee) Medical College, he joined the Service as an intern 
and by 19 13 had progressed through the ranks to Surgeon. During 
the Spanish-American War, Fricks monitored U.S. troops to prevent 
the introduction of yellow fever into the United States. While on quar- 
antine duty two years later, he suffered a bout with the infamous 
Yellow Jack. From his medical school days, Fricks had been interested 
in microscopical investigations. Like McCHntic before him, Fricks ar- 
rived in Montana, in the spring of 191 3, only to be surprised by new 
political developments relating to spotted fever. 

When the U.S. Bureau of Entomology had withdrawn from spotted 
fever work, Robert A. Cooley had been unable to continue his own 
tick eradication efforts. Taking a new approach, Cooley proposed to 
F. B. Linfield, director of the Montana agricultural experiment station, 
that a state entomological commission be established to supervise tick 
eradication work in the Bitterroot. Linfield concurred and suggested 
that the board be comprised of Cooley as state entomologist, Tuttle 
as secretary of the state board of health, and— to serve as a buffer 



Tick Eradication Efforts, ipii-ipzo 



89 



between the two strong-willed men— W. J. Butler, the state veterinar- 
ian. State Senator Fred Whiteside agreed to sponsor the bill in the 
19 1 3 session of the Montana state legislature. Working with Whiteside, 
Cooley ensured that the bill was broadly worded, allowing the board 
to investigate other disease-carrying insects as well as the spotted fever 
tick. The new board was needed, Cooley stated, because there existed 
no official state agency "clothed with all the legal authority needed to 
prescribe and enforce the necessary rules and regulations" for the 
eradication of the spotted fever tick. Approved on 18 March 191 3, 
the new law authorized a Montana State Board of Entomology to 
"take steps to eradicate and prevent the spread of Rocky Mountain 
tick fever. Infantile Paralysis and all other infections of communicable 
diseases that may be transmitted or carried by insects. '"^^ 

Smooth functioning of the new state board was fostered by the 
resignation of Thomas D. Tuttle as secretary of the Montana State 
Board of Health. His term ended in December 19 12, and when Gov- 
ernor Samuel V. Stewart offered him a position as first director of the 
Montana Tuberculosis Sanatorium, he accepted. For all of his efforts 
on behalf of pubUc health, including a state food and drug law as well 
as the sanitorium, the Montana Medical Association awarded Tuttle 
its first Ricketts Memorial Medal, established to honor the revered 
research martyr."^^ Tuttle appeared happy to escape the continual bat- 
tles with Cooley, which, he noted, had contributed to a chronic stomach 
ulcer. As his successor he recommended WiUiam Forlong Cogswell, a 
physician in Livingston, Montana, and a Canadian native trained at 
Dalhousie University Medical School in Halifax, Nova Scotia. Cogs- 
well was duly elected at a special meeting of the state board of health 
on 16 December. Fearing that Cogswell would continue Tuttle's pol- 
icies, Cooley did not initially inform him about the proposed board 
of entomology law. Linfield, however, actively lobbied Cogswell and 
succeeded in persuading him to testify in favor of the bill's passage.^^ 

At the first meeting of the Montana State Board of Entomology, a 
defensive Cooley recommended that the U.S. Bureau of Entomology, 
which had recently received a fifteen-thousand-dollar appropriation 
for use in spotted fever tick eradication, be given exclusive rights to 
the tick eradication work, thus shutting the U.S. Public Health Service 
out of any involvement. The two other board members, Cogswell and 
the state veterinarian, W. J. Butler, however, consulted with Governor 
Stewart and formulated a plan by which more harmonious relations 
might be maintained between the state and the two federal agencies. 
Their proposal, carried over Cooley's objection, called for a conference 
with representatives of the two federal agencies to work out an ac- 



90 



Rocky Mountain Spotted Fever 



ceptable compromise. At the meeting, held ii April 19 13, W. D. 
Hunter of the U.S. Bureau of Entomology and Lunsford D. Pricks of 
the U.S. Public Health Service agreed to divide tick control w^ork in 
the Bitterroot Valley geographically. A line of division w^as set at Big 
Creek, southw^est of Stevensville. Territory north of this line was de- 
clared the province of the U.S. Bureau of Entomology, w^ith Cooley 
in charge of the w^ork. The southern part of the valley w^ould be under 
the jurisdiction of Fricks, representing the U.S. PubHc Health Service. 
On instructions from Service headquarters, however, Fricks was to 
report only to the secretary of the Montana State Board of Health.^^ 

To residents of the Bitterroot, this division must have seemed pe- 
culiar, especially since each agency advocated different measures to 
rid the valley of its scourge. Initially the entomologists stood fast by 
their contention that within two or three years livestock dipping alone 
would reduce the spotted fever tick to levels such that the disease 
would no longer be a threat. Destruction of the small rodents that 
harbored the immature stages of the tick was described only as "an 
important secondary means of combating the tick." In contrast, Fricks, 
representing the medical position, held that a vigorously prosecuted, 
three-pronged program was necessary. Of equal importance to live- 
stock dipping, Fricks argued, was an active campaign to destroy small 
rodents. In addition, he insisted that legislation should be passed re- 
stricting domestic stock from grazing on the infected west side of the 
river during tick season. In spite of these differences, the Northwest 
Tribune reported the conference as the beginning of a concerted war 
on the wood tick, never mentioning spotted fever.^^ 

These different approaches led to a second conference on 18 July. 
Cooley argued that the division of responsibility was not proving 
effective. Fricks caused dissension, Cooley alleged, by claiming that 
"dipping would not get rid of the tick in thirty years." Cooley further 
asserted that Fricks did "not know any more about entomology" than 
Cooley did about medicine. Cooley's plan was to divide the work 
along professional speciaHzations: the U.S. Bureau of Entomology 
should solely manage tick control operations; the U.S. Public Health 
Service, laboratory experiments; and the U.S. Bureau of Biological 
Survey, which Cooley hoped would reactivate its participation, ground 
squirrel eradication.^^ 

Believing that it was "not fitting" for two federal agencies to "haggle 
with the state authorities" over the work, Fricks recommended to 
Surgeon General Blue that the U.S. Public Health Service withdraw 
from tick control work entirely. L. O. Howard, chief of the U.S. Bureau 
of Entomology, Hkewise suggested to Blue that the bureau's generous 



Tick Eradication Efforts, 1911-1910 



91 



appropriation for tick eradication work would surely be renewed and 
would provide ample funds for the work. Howard argued that "perfect 
harmony" could be achieved if the Service did pathological work and 
left tick eradication to the entomologists/"^ 

At U.S. Pubhc Health Service headquarters, reaction to this new 
proposal was uniformly negative. Service leaders had battled since the 
1870s for primacy in federal health matters, and they were not inclined 
to yield any of their hard-won authority. Blue notified Howard that 
the Service intended to continue its work and remarked that the sur- 
render of functions was hardly cooperation, "at least in the best sense 
of the term." In a memo to his superior. Secretary of the Treasury 
WiUiam G. McAdoo, Blue reiterated the Service's longstanding position 
that spotted fever, in all its aspects, was essentially a public health 
problem. "It would be as logical," Blue wrote, "to turn over to the 
Bureau of Entomology the suppression of yellow fever epidemics, be- 
cause the disease is spread by mosquitoes." If such a precedent were 
set, "it would also be necessary to turn over to the Bureau of Animal 
Industry the dipping of cattle because several domestic animals harbor 
the tick, [and] also a part of this work would have to be given to the 
Forestry Service because ticks are found in the Forest Reserves bor- 
dering the Bitter Root Valley."^^ Fricks, furthermore, was advised to 
revise his position, letting it be known that the Service would not 
withdraw "without a fight." Observing that Cooley would probably 
attempt to "slip the skids under you at the first opportunity," Blue 
cautioned Fricks, "Whatever you do, don't let any of them back you 
out of there."^^ 

For five years, from 19 13 through 19 17, two federal agencies ad- 
vocating two separate programs combated a tick known by two names. 
Since the dipping of livestock was the most visible aspect of both 
agencies' efforts — and the one most directly affecting the livelihood of 
valley residents— any problem with this undertaking jeopardized the 
future of the entire program. Unfortunately, the mild dipping solution 
available on the open market, which contained 0.169 percent of ar- 
senious oxide, proved to be too weak to kill engorged female ticks. 
When the strength was increased to 0.228 percent— the concentration 
commonly used throughout the south to treat Texas cattle fever— the 
solution burned the hides of Montana cattle. As the search continued 
for an acceptable concentration, other quality control problems de- 
veloped. On one occasion, for example, the kerosene and water in the 
dip separated when it was allowed to stand unused for several hours. 
When cattle were subsequently immersed, the solution burned the 
cows' udders.^^ 



92 



Rocky Mountain Spotted Fever 




An arsenical solution killed ticks on the hides of livestock in the fifteen 
seconds it took to swim through the concrete dipping vat. Rocky Mountain 
wood ticks, however, preferred to attach themselves around the horns and 
ears of cattle. It was nearly impossible to submerge the heads of the cattle 
for longer than one second, which was insufficient time to do serious harm 
to engorged female ticks. (Courtesy of the National Archives and Records 
Administration.) 



These difficulties, which might be expected in any new undertaking, 
generated significant ill-feeling in the owners of the afflicted stock. 
Local ranchers, who remained skeptical of the tick theory and who, 
during tick season, blamed the dip for any sickness or death among 
their stock, filed several lawsuits. The state attorney general exacer- 
bated already strained relations when he ruled that the state was not 
hable for accidental death or damage to the ranchers' stock caused by 
the program. By 19 14 a less damaging arsenic dip was identified, 
but Bitterroot Valley ranchers who sustained real or imaginary losses 
from the dipping procedure were not inclined to be patient.^^ 



Tick Eradication Efforts, ipii-ipzo 



93 



In June 19 13 the U.S. Public Health Service's vat at Hamilton was 
destroyed by vandalism, and later that month the U.S. Bureau of 
Entomology's vat at Florence was dynamited. No precipitating incident 
was traced to the Hamilton attack. In Florence, however, Carl and 
George Wemple, brothers aged nine and eleven who assisted at the 
vat on their family's property, had fallen ill with spotted fever. After 
George died, the vat was destroyed. ^° During his investigation of the 
incident, Cooley was advised that the people of Florence, whom he 
termed in exasperation "an ignorant, mean lot," felt no remorse over 
the dynamited vat. In fact, since many of them rejected the tick trans- 
mission theory outright, there existed "quite a hard feeling among 
them" about the dipping program. In response to the incidents, the 
Montana State Board of Entomology called for vigorous prosecution 
of anyone vandalizing the dipping vats. The board also increased its 
educational efforts among ranchers, utilizing circulars and demon- 
strations. Within a year the board reported that public attitude in the 
Stevensville and Florence districts had been so changed that it was no 
longer necessary to argue the question of tick transmission of spotted 
fever. Residents of the Lo Lo canyon area remained unconvinced and 
never installed a vat, but they refrained from taking violent action 
against other facilities in the program.^^ 

To determine the relative extent of tick infestation in different sec- 
tions of the Bitterroot and to serve as a check upon the efficacy of tick 
eradication measures, Willard V. King and Lunsford D. Fricks con- 
ducted tick surveys in their respective control districts. King examined 
livestock for tick infestation in the U.S. Bureau of Entomology's dis- 
tricts; Fricks undertook a more ambitious survey, gathering ticks from 
the riverbank, from the rolling benchlands, and even from the high 
reaches of the Bitterroot Mountains. He found practically no ticks on 
the cultivated lands, a zone of heavy infestation in the hills where 
horses and cattle were allowed to range, a zone of "moderate" infes- 
tation—up to 7,040 ticks per square mile— just above the range of 
domestic animals, and, finally, an extraordinarily heavy infestation, 
estimated at millions of ticks per square mile, in "goat country," the 
high mountainous area where large numbers of Rocky Mountain goats 
ranged. Because heavy infestations at the higher elevations constantly 
threatened the tick eradication efforts in the valley, Fricks concluded 
that ultimate success would depend upon "the creation of a tick-free 
zone extending as far as possible up into the Bitter Root Mountains. "^^ 

Both groups also took a census of livestock in the valley. Surprisingly, 
it revealed that relatively few animals ranged over the tick-infested 
areas. In the Victor district, for example, there were 1,865 animals, 



94 



Rocky Mountain Spotted Fever 



but only 350 cattle and 50 horses required regular dipping. The re- 
maining 1,500 animals were either pastured on the tick-free bottom- 
lands or classified as dairy cows or work horses, animals exempted 
from dipping if their owners agreed to remove ticks by hand.^^ 

Since there were so few animals that actually needed to be dipped, 
Fricks strongly recommended that the grazing of livestock be restricted 
by law during the spring. "It would be cheaper," he noted, "to prohibit 
such grazing entirely than to construct and operate dipping vats." The 
Montana State Board of Entomology, however, consistently refused 
to adopt restrictions, arguing that they would generate hostihty among 
the citizenry. After one meeting at which restrictions were considered 
and soundly defeated, Cooley wrote to King that "each member of 
the board, speaking for himself, said that he did not care to take the 
responsibility of voting such a regulation through. "^"^ 

Fricks also maintained that the labor costs of ground squirrel erad- 
ication, viewed by Cooley as excessively expensive, could be controlled 
by inducing landowners themselves to do the work. To this end he 
procured twelve "squirrel destroyers," or carbon bisulphide pumps, 
like those used by the Service in the antiplague campaign on the Pacific 
coast. Farmers were offered free use of the pump for a specified pe- 
riod.^^ 

In addition, Fricks suggested the novel idea that west side landowners 
substitute bands of sheep for their horses and cattle. Sheep had been 
grazed closely on the east side of the valley since about 1890, Fricks 
noted, and tick infestation there was practically nonexistent. He con- 
cluded that sheep grazing might be an economical method to rid the 
west side of ticks as well. It was known, moreover, that lanolin in 
sheep wool was repugnant to ticks and that the density of the wool 
made it difficult for male and female ticks to locate one another for 
mating. In an experiment Fricks conducted during 19 13 with one small 
band of sheep, over 87 percent of 295 ticks placed in the wool of 
unshorn sheep were recovered dead. Moreover, most ticks recovered 
from sheep grazing naturally were found dead, and many engorged 
females appeared to be unfertilized.^^ 

More importantly, sheep were known to eat the brush vegetation 
in which ticks dwelled. By herding them back toward the foothills as 
they grazed, Fricks argued, a habitat alien to the tick would be pro- 
duced. Other large domestic and wild animals would be removed from 
sheep ranges, and some ticks would be destroyed simply by the grazing 
of sheep. Finally, Fricks observed that if further experiments with sheep 
proved successful, tick eradication could be placed on an industrial 



Tick Eradication Efforts, ipii-ipzo 



95 



basis. This would significantly diminish the cost of spotted fever control 
work to the federal and Montana taxpayers. 

The chilly reception given to Fricks's theory by Cooley and King 
reflected the ongoing tension between the U.S. Public Health Service 
and the Montana State Board of Entomology. At Cooley's request, 
King repeated Fricks's experiment with a band of six sheep. His findings 
indicated that "the number of ticks which developed on the sheep 
were more than sufficient to maintain a normal supply." King did not 
explore whether sheep grazing might control the underbrush that har- 
bored ticks. To Cooley, King wrote that "only in a special combination 
of circumstances can sheep be relied upon to effect reduction of the 
tick." He did not elaborate on what these circumstances were or 
whether they existed in the Bitterroot.^^ 

Because Fricks's plan remained experimental and was never sup- 
ported on a wide scale, moreover, it is difficult to assess its potential 
merits. Initially there was optimism among Bitterroot residents, and 
some ranchers added sheep to their stock. Had the plan proved 
efficacious, of course, it would have merited praise for cost-effective- 
ness. Under the strained circumstances, no adequate trial was ever 
conducted. 

By 19 1 6 experience had demonstrated that rodent control and graz- 
ing restrictions would indeed be necessary if the Rocky Mountain wood 
tick was to be eliminated from the Bitterroot Valley. The "starvation" 
method used so successfully against the Texas cattle fever tick, Mar- 
garopus annulatus, simply did not work in Montana. That tick spent 
its entire life cycle on one animal, hence dipping killed all stages. The 
spotted fever tick, in contrast, fed on different animals in the larval, 
nymphal, and adult stages. The Texas cattle fever tick died after one 
year if unable to reach a host, but the hardier Rocky Mountain wood 
tick could remain unfed for three years or longer, after which it would 
feed and reproduce if placed on a host.^° 

Furthermore, Montana's climate interfered with dipping operations 
during the crucial early spring period. "One warm sunshiny day in 
March is sufficient to bring forth the adult ticks," Fricks wrote after 
one season in Montana, "and when this is followed by a week or more 
of freezing weather . . . during which it is impossible to use the dip, 
some females may be fertilized and drop off for egg laying before it 
is possible to destroy them." CompHcating this situation further was 
the tick's predilection for attaching itself to cattle "around the horns, 
ears, and high up on the neck." The average time required by a cow 
to swim through the Victor vat was found to be fifteen seconds, and 



96 



Rocky Mountain Spotted Fever 



all ticks submerged that length of time were killed or incapacitated. 
The cattle, however, swam with their heads out of the solution. It was 
almost impossible to submerge them completely for longer than one 
second, a period insufficient to do serious harm to the engorged females 
in any strength that could be borne by the livestock. 

The entire spotted fever situation changed "materially" in the spring 
of 19 1 5, when the disease was reported from eastern Montana. "To 
the surprise of us all," Cooley noted, two cases appeared in the northern 
part of Gallatin County, near Bozeman, and a few were reported near 
Billings. "Something hke ten or a dozen" cases were reported from 
the flat, sagebrush country in eastern Montana near Miles City and 
others from Richland County, which bordered North Dakota.^^ Of 
thirty-five cases reported in 19 15, only seven occurred in the Bitterroot 
Valley and Missoula areas, while twenty-three were reported from the 
newly discovered eastern areas of infection. The disease seemed to 
take the mild Idaho form in the eastern counties, for only two deaths 
were reported, compared with five among the Bitterroot Valley cases. 
W. F. Cogswell, secretary of the Montana State Board of Health, told 
the press that spotted fever had probably spread into eastern Montana 
from Wyoming. "The new cases are occurring along the Powder river, 
which has its source in Wyoming."^^ 

Both the U.S. Public Health Service and the Montana State Board 
of Entomology launched investigations of this new appearance of spot- 
ted fever. The Service had detailed a young assistant surgeon, Roscoe 
Roy Spencer, to assist Fricks in 1915; Fricks sent Spencer to Miles 
City, Montana, to confirm the diagnosis of spotted fever by inoculating 
guinea pigs with the blood of patients. The Montana State Board of 
Entomology focused on the ecology of eastern Montana spotted fever. 
Cooley assigned the project to Ralph Robinson Parker, a young as- 
sistant entomologist employed by the state board. Ten years later, these 
two "R.R.s," as they were often called, would collaborate on a vaccine 
against spotted fever, but at the end of the summer of 19 15, Spencer 
returned to his rotating assignments as a new Service officer. Parker, 
on the other hand, continued to be intimately involved with spotted 
fever control work. 

The twenty-seven-year-old son of a Massachusetts physician, Parker 
was a graduate student in entomology at Cooley's alma mater, the 
Massachusetts Agricultural College. In 19 14, Cooley had written to 
his mentor H. T. Fernald, seeking the name of a student who might 
be interested in studying flies and their relation to typhoid fever for 
the Montana State Board of Entomology. Fernald recommended 
Parker, and Cooley recruited him to work during that summer in the 



Tick Eradication Efforts, i^ii-i^zo 



97 



Yellowstone valley. An extremely conscientious worker and meticulous 
record keeper, Parker surveyed the eastern Montana spotted fever 
situation in 19 15 and returned in 19 16 with his Ph.D. in hand to 
establish a field station at Powderville, Montana. With the assistance 
of his bride, Adah Nicolet Parker, the young entomologist investigated 
topography and vegetation in addition to the local species of ticks and 
their animal hosts. His most disturbing finding was that in this area, 
small animals, particularly rabbits, served as hosts to adult as well as 
immature stages of the tick. Dipping domestic stock would be futile 
if adult ticks matured on the widely distributed rabbits. The following 
year Parker gathered additional information in Musselshell, Montana, 
but he offered no concrete suggestions for tick control. 

As it became manifest that spotted fever would not be eradicated 
as simply and quickly as had Texas cattle fever, the Montana State 
Board of Entomology reluctantly adopted a regulation restricting, with 
some exceptions, the grazing of livestock in the Bitterroot Valley be- 
tween I March and 15 July each year. Ground squirrel destruction 
also became a more important part of the U.S. Bureau of Entomology's 
control program. In the fall of 19 16 a newspaper article reported on 
the expanded control program with no mention that the U.S. Public 
Health Service had advocated such methods since 191 1. Fricks reacted 
to this article as Tuttle had before him: the entomologists, he believed, 
were claiming credit that rightly belonged to others. Fricks protested 
the perceived injustice, but the entomologists maintained that they had 
come to their conclusions independently.^'' 

More substantive was an ongoing disagreement between Fricks and 
the Montana State Board of Entomology over grazing restrictions. The 
board's regulations authorized exemptions for persons who grazed 
their stock on state land under long-term leases. The state was loath 
to cancel these leases, even though many of the lessees were absentee 
owners, and the Montana State Board of Entomology argued for the 
exemptions on the grounds that some of the lessees had few other 
means of income. Fricks countered that this argument was wholly 
unacceptable. "By the same reasoning, many practices, such as piracy 
and highway robbery for instance, which are now under the ban of 
the law might easily be condoned. "^^ 

In December 19 16, Fricks appealed to federal officials in Washington 
to put pressure on the state authorities. William P. Malburn, writing 
for the secretary of the treasury, accordingly reminded Governor Sam- 
uel V. Stewart of the "large sums of money which this Department 
has expended in the endeavor to control this disease in the State of 
Montana." He urged state authorities to adopt strict grazing restric- 



98 



Rocky Mountain Spotted Fever 



tions immediately. The state board of health secretary, W. F. Cogswell, 
replied to this letter, explaining the exceptions, but Treasury Secretary 
William G. McAdoo was not appeased. Reiterating the federal financial 
investment, McAdoo warned that the state must enact and enforce 
more stringent grazing restrictions if the work of the U.S. Public Health 
Service was to be continued. 

Even as this exchange was occurring, the United States was being 
pulled relentlessly into World War I. President Woodrow Wilson had 
been reelected on the slogan "He Kept Us out of War," but a German 
declaration of unrestricted submarine warfare in January 19 17, fol- 
lowed by the actual torpedoing of several ships, induced Wilson to 
change his position. By 6 April 19 17 both houses of Congress had 
voted to declare war. The following day, at a meeting of the Montana 
State Board of Entomology, Fricks took the first step toward disen- 
gaging the U.S. Pubhc Health Service from its commitment in Montana. 
He introduced a resolution declaring a portion of the territory on the 
west side of the Bitterroot tick free. In his report of this meeting to 
the surgeon general, Fricks noted that Willard V. King had admitted 
"for the first time, that the dipping of domestic animals had proven 
impracticable as a tick eradicative measure in the Bitter Root Valley." 
Furthermore, he continued, "the Board passed a resolution favoring 
the introduction of sheep for this purpose." Fricks recommended that 
the Service discontinue its work after 30 June 19 17, since its position 
had been "vindicated." Surgeon General Blue concurred and informed 
Cogswell that the Service was withdrawing. Fricks, who had grown 
to love the Bitterroot Valley, was ordered to Memphis, Tennessee, to 
take charge of malaria control work for the duration of the war.^° 

After the withdrawal of the U.S. Public Health Service, the state 
board of entomology voted unanimously to ask the U.S. Bureau of 
Entomology to take over control work for the entire valley. Cooley 
wrote to Congresswoman Jeanette Rankin, whose father had died of 
spotted fever in 1904, for assistance in securing a larger appropriation 
for the work. The U.S. Bureau of Entomology, however, had changed 
its mind about participating. "The matter primarily is a question of 
public health," stated the secretary of agriculture in his reply to Ran- 
kin's inquiry. "It is believed that the question of eradication is one 
which should be dealt with by the State authorities and, if the assistance 
of the Federal Government is needed, the cooperation of the Health 
Service should be sought. While the Bureau of Entomology heretofore 
has done some work in connection with the eradication of the disease, 
it seems advisable hereafter for that Bureau to deal only with the 
entomological phases of the problem, such as the study of the fife 



Tick Eradication Efforts, i^ii—i^io 



99 



history and habits of the tick and similar matters. "^^ 

The absence of any federal assistance left Montana in a financially 
difficult position. The state board of entomology resolved to continue 
the work and in the spring of 191 8 appointed Ralph R. Parker to take 
charge of control measures in the Bitterroot. During the previous fall, 
Parker had spent two months at Harvard University in productive 
research on the anatomy of ticks and was clearly the most knowl- 
edgeable entomologist available to Montana authorities. He worked 
with little money and few^ assistants, since many young men had vol- 
unteered for service in the military. The vats at Stevensville and Blodgett 
Creek leaked, the Victor vat needed repairs, and there was a problem 
getting water to the Florence vat. Local committees, however, sup- 
ported Parker, advocating enforced dipping and expressing willingness 
to assume a larger share of the cost.^^ 

After directing the control program for only a short time, Parker 
concluded that its priorities needed to be reordered. "I am seriously 
of the opinion," he wTote to Cooley, "that the work here will have to 
undergo a radical change ... if we are to get real results. Frankly I 
am in favor of cutting out the dipping absolutely. I have no faith in 
it." He pointed out that Montana's cold spring made dipping impos- 
sible during late February and early March. "It seems to me that under 
the best of conditions ... we cannot, by dipping get more than a scant 
25% of the ticks that actually engorge on the animals." He concluded 
that ground squirrel control coupled with restrictions on grazing con- 
stituted a better approach. 

The entire program, moreover, was under some strain during this 
period. In spite of five years of tick control efforts, spotted fever had 
not been eradicated. There continued to be some opposition from some 
stock owners to grazing restrictions, and the game warden opposed 
the "indiscriminate" use of poisoned grain because of the hazard it 
posed to birds. In support of the program, Cooley argued that spotted 
fever cases had been reduced from eleven to three from 1913 to 1918. 
King published data indicating that the number of ticks had been 
reduced 80—90 percent, although he noted that the reduction varied 
from area to area. Given this unsettled situation, Cooley soHcited 
testimonial letters from valley residents for the board's third biennial 
report, presumably to buttress the board's appropriation request.^"^ 

Although Montana lawmakers did increase the budget of the board 
for 1919 and 1920, they curtailed the appropriation in 1921.^^' Cooley 
and Parker had hoped to launch a broad-scale study of spotted fever 
in nature as a basis for developing more efficient and permanent meth- 
ods to destroy the tick. In 1920, furthermore, Cooley recommended 



lOO 



Rocky Mountain Spotted Fever 



that tick control operations be extended into the mountainous regions, 
including possible extermination of the Rocky Mountain goat, which 
had been shown to serve as a major natural host for adult ticks. A 
few years later, this proposition became a minor cause celebre as 
wildlife lovers came to the goat's defense. The author of a Northwest 
Tribune article entitled "The Mountain Goat or Taxpayers Goat" 
argued that the entire tick control program was a sink for money and 
had produced scant results. Unless it could be shown definitively that 
the program was effective, "a pause should be made before continuing 
to throw money into the bottomless well."^^ 

The reduced appropriation in 192 1 ironically coincided with a pre- 
cipitous rise in the number of spotted fever cases in the Bitterroot— 
from four in 1920 to eleven in 1921. All eleven cases, moreover, proved 
fatal. Among the victims were two prominent Lo Lo residents, Mon- 
tana State Senator Tyler Worden and his wife, who was president of 
the Montana Federation of Women's Clubs. All but two of the 1921 
cases were acquired in the canyons running back into the Bitterroot 
Mountains, which indicated that although the tick control program 
had contributed to the safety of residents within the control districts, 
spotted fever remained a hazard in the valley. Worried state officials, 
fearing that the disease might be in a resurgence, petitioned the U.S. 
Public Health Service to return. 

A decade of tick control efforts had reduced the tick population but 
had not succeeded in ridding the Bitterroot of spotted fever. In assessing 
the work of this period, it is necessary to recall that in 19 10, when 
the hope for a medical approach to spotted fever control seemed to 
die with Howard Taylor Ricketts, vector control offered the most 
promising method of combating the disease. Similar efforts against 
yellow fever and Texas cattle fever had produced stunning results, and 
doubtless Robert A. Cooley and his associates hoped to rid western 
Montana of its scourge with the same simple, effective measures. Cool- 
ey's personal clash with Thomas D. Tuttle, unfortunately, led the 
ambitious entomologist into a combatant posture with the U.S. PubHc 
Health Service that surely retarded adoption of control methods other 
than livestock dipping. The insistence of the Service that its officers 
deal only with the state health officer rather than with the Montana 
State Board of Entomology, moreover, exacerbated the situation. In 
retrospect, these quarrels may have cost Montana and federal taxpayers 
additional money, but at that time the control efforts themselves ap- 
peared to be the only recourse available by which virulent spotted 
fever in the Bitterroot could be attacked, and thus they provided a 
means for some type of active response against the deadly affliction. 



Chapter Six 



A Wholly New Type 
of Microorganism 

Nature makes so gradual a transition from the inanimate to the animate 
kingdom that the boundary lines which separate them are indistinct and 
doubtful. 

Aristotle, Historia Animalium 



From 1902, when Louis B. Wilson and William M. Chowning 
launched the first scientific investigation, until 19 10, when Howard 
Taylor Ricketts died, bacteriological techniques had been the methods 
of choice among investigators of Rocky Mountain spotted fever. Using 
the microscope, blood smears, staining and fixing techniques, and 
animal inoculations, bacteriologists had demonstrated tick transmis- 
sion and identified a suspected organism. Conclusive proof that this 
microorganism caused spotted fever eluded early researchers, however, 
because they could not cultivate the organism on artificial media, a 
requirement laid down by Robert Koch to demonstrate bacterial cau- 
sation.^ Serum therapy used successfully against some other diseases, 
furthermore, had failed to produce a dramatic cure for spotted fever, 
and, in any case, efforts to develop preventive or therapeutic medical 
strategies had died with Ricketts. With the armamentarium of bac- 
teriology so depleted, investigators sought new approaches to identify 
spotted fever's mysterious etiological agent. During the second pro- 
ductive period of laboratory research on spotted fever, the methods 
of pathology supplanted those of bacteriology in unraveUng this por- 
tion of the riddle. 

The beginning of systematic study in disease pathology is usually 
traced to the work of Giovanni Battista Morgagni, an eighteenth- 
century professor of anatomy at the University of Padua. Morgagni 
noted particular lesions found at autopsy and suggested that they might 
explain clinical symptoms. His observations stimulated a systematized 
search to correlate pathological lesions with symptoms. By the mid 



lOI 



I02 



Rocky Mountain Spotted Fever 



nineteenth century, sufficient data had been gathered to distinguish 
among many diseases with similar characteristics. With improvements 
to the microscope after 1830, it became possible to study the fine 
structures of the body. In 1858, building on concurrent discoveries 
that plant and animal tissues w^ere comprised of cells, Rudolf Virchow^ 
postulated the doctrine of cellular pathology — that disease occurred 
because of interaction between living cells and disease agents. After 
1880, when the light microscope was perfected and the discovery of 
bacteria stimulated the development of staining methods and other 
techniques, careful studies of the cellular pathology— or histology, as 
it came to be called— of diseased tissue became possible. 

Since the most pressing need during the early decades of histological 
study was information about such major infectious diseases as tuber- 
culosis and typhoid fever, rare maladies such as Rocky Mountain 
spotted fever received httle attention. Aside from Wilson and Chown- 
ing's autopsy notations on gross pathology, E. R. LeCount, an associate 
of Ricketts at Rush Medical College in Chicago, had by 19 16 produced 
the sole histological study of spotted fever. LeCount's work was not 
exhaustive but rather constituted the initial findings of a larger study 
abruptly terminated by Ricketts's death. The microscopic changes 
caused by spotted fever infection, LeCount noted, were of two sorts. 
First, diffuse lesions, affecting entire groups of organs, were similar to 
the changes caused by other infectious diseases. Second and more 
important, he believed, were the "focal lesions" connected with the 
occlusion of blood vessels in sections of the skin, liver, kidney, spleen, 
and adrenal glands. Although LeCount also found capillaries and small 
veins in the lung and heart practically occluded with leukocytes, he 
concluded that "there were no serious consequences of these conditions 
with exception of minute hemorrhages beneath the endocardium." 
Likening the changes caused by excessive leukocytes and the focal 
lesions to those seen in typhoid fever, LeCount speculated that they 
were probably caused by the "action of the toxin of this disease." 
Some of the "so-called 'endothelial toxins' " he noted, were believed 
to be "Hberated from the bodies of bacteria."^ 

In January 191 6, Simeon Burt Wolbach, a pathologist at Harvard 
University School of Medicine, became interested in Rocky Mountain 
spotted fever. Trained under the distinguished pathologists William T. 
Councilman and Frank B. Mallory, Wolbach had in 191 1 participated 
in studies of trypanosomiasis, parasitic protozoa, and tropical ulcers 
in Gambia, then a British colony, on the west coast of Africa.^ The 
publications resulting from this work earned Wolbach promotions at 
Harvard, to associate professor of bacteriology in 19 14 and to associate 



A Wholly New Type of Microorganism 



103 



professor of pathology two years later. Wolbach began his work with 
strains of spotted fever obtained from Surgeon Lunsford D. Fricks of 
the U.S. Public Health Service, who was continuing his own bacteri- 
ological studies in addition to implementing tick control efforts.^ 

About the same time, Hideyo Noguchi, a bacteriologist at the Rock- 
efeller Institute for Medical Research in New York also entered spotted 
fever investigations.^ Having achieved prestigious status as a full mem- 
ber of the Rockefeller Institute in 19 14, Noguchi was well known for 
his early work on snake venoms and his more recent work on spi- 
rochetes, especially on Treponema pallidum, the cause of syphilis. 
According to Noguchi's biographer, Isabel R. Plesset, Noguchi cast 
about during 191 5 for an interesting new problem and selected Rocky 
Mountain spotted fever, which resembled his homeland's tsutsuga- 
mushi disease. In late 191 5 or early 19 16, Noguchi visited Fricks at 
the Hygienic Laboratory and obtained strains of spotted fever in guinea 
pigs. The entrance of this more senior, celebrated Rockefeller re- 
searcher into the spotted fever field prodded both Wolbach and Fricks 
to speed up their work.^ 

Fricks, who had already studied spotted fever for three years, has- 
tened to pubhsh the results of his microscopical research. In early 
19 1 6, at medical meetings in Missoula and Salt Lake City, Fricks 
announced that he had consistently found "extra corpuscular granules" 
in the blood of human and animal victims of spotted fever. These, he 
stated, occurred singly and in pairs and, when stained by the Giemsa 
method, appeared bright red and were highly refractile. He also found 
similar bodies "within or in close proximity to" the red blood cells. 
Those inside the red cell, he said, were "round or slightly elongated 
red chromatin bodies partially surrounded by or in close approxi- 
mation to a somewhat larger deep-blue staining body." All of the 
chromatin bodies were one micron or less in diameter. Fricks concluded 
that the "morphological and tinctorial characteristics" of these bodies 
implied that they were of a protozoan nature.^ 

Wolbach, although just beginning his studies, had little regard for 
Fricks's presumed organism. Corresponding with the secretary of the 
Montana State Board of Health, W. F. Cogswell, Wolbach confided, 
"I am on an entirely different track and have great hopes of contributing 
something of importance." It would take time, he continued, to confirm 
his hypotheses, because he was using the "peculiarly difficult tech- 
nique" of teasing apart tick tissues rather than crushing them. Initially, 
Wolbach had planned to supplement these laboratory studies of tick 
and guinea pig tissues by travefing to Montana to study human cases 
of the disease, and to this end he had requested that the Montana 



I04 



Rocky Mountain Spotted Fever 




S. Burt Wolbach, a pathologist at Harvard University School of Medicine, 
described spotted fever as an infection of the circulatory system and identi- 
fied the causative organism in the tissues of infected ticks, experimental ani- 
mals, and human victims. Wolbach also recognized that the rickettsial 
organisms could not be cultured on lifeless media but required living cells 
in which to grow and replicate. (Courtesy of the National Library of 
Medicine.) 



State Board of Entomology detail Ralph R. Parker to assist him. Robert 
A. Cooley, however, wanted Parker to spend the summer in Powderville 
studying Eastern Montana spotted fever, just recognized the previous 
year. All hope of studying human cases evaporated when Wolbach 
suffered an attack of appendicitis with compUcations that precluded 
any travel.^ 

Despite this setback, Wolbach determined to pubHsh preHminary 
findings based solely on studies of tick and guinea pig tissues rather 
than risk losing priority to Noguchi.^ His research had revealed, Wol- 
bach wrote to Cooley, that spotted fever affected "primarily the pe- 
ripheral blood vessels" and that the rash and necrosis were "secondary 
to the vascular lesions." These findings were "entirely consistent and 
confirmatory of clinical descriptions of the disease," he continued, and 
he expressed surprise that no one had previously paid attention to the 
tissues, which he regarded as essential. 

In mid 191 6, Wolbach published two papers on these preliminary 
findings in the Journal of Medical Research. In the first he described 
a Gram-negative organism from 0.2 to 0.5 microns wide that occa- 



A Wholly New Type of Microorganism 



105 



sionally occurred "in large numbers" and was concentrated in the 
"smooth muscle cells of affected arteries and veins." With Giemsa's 
stain the organisms stained "bluish," this being "in marked contrast 
to most bacteria, which take an intense reddish purple stain." Since 
this reddish purple coloration — usually achieved by using the Ro- 
manowsky stain— was regarded as the chromatin staining reaction, 
Wolbach noted that he was "somewhat at a loss to understand the 
description 'chromatin staining' by Ricketts as applied to this orga- 
nism." This initial paper was followed a few months later by a second 
preliminary report on the organism in ticks. Although he had observed 
the organism throughout tick tissues, Wolbach concluded that there 
was no cellular reaction in the ticks to the presence of the parasites, 
"even when present in enormous numbers." This was indicative that 
the organism had evolved a symbiotic relationship with its tick host 
over centuries. 

Ironically, although it was Noguchi's perceived competition that 
stimulated the publication of Fricks's and Wolbach's papers, Noguchi 
himself did not make much progress during 19 16 on spotted fever. 
His attention had turned instead to studies of the spirochete that caused 
Weil's disease, an organism that he identified as a new genus, Lep- 
tospira. Having read the papers published by both Fricks and Wolbach, 
Noguchi was inclined to support Fricks's protozoan theory. When he 
received a slide of Fricks's presumed organism, Noguchi replied that 
he, too, had "seen similar bodies several times" in his own work. It 
is not surprising that Noguchi, as a speciahst in spirochetes, some of 
which were known to be arthropod-borne, was receptive to the pos- 
sibihty of a spotted fever organism with protozoan characteristics.^^ 

Smarting under Noguchi's preference for Fricks's protozoan theory, 
Wolbach characterized Noguchi and his colleagues as "the skeptical 
autocrats at the Rockefeller Institute." Such feelings of institutional 
rivalry also emerged at the Hygienic Laboratory. The director, George 
W. McCoy, wrote encouragingly to Fricks that no one at the laboratory 
was concerned about Wolbach's publication. They had concluded that 
Wolbach's organism was probably the same organism Fricks had seen. 
"Unless Noguchi has something a whole lot better than Wolbach," 
McCoy continued, "we should worry." He noted that the laboratory's 
histologist had thus far been unable to verify Wolbach's findings of 
the organism in tissues. Furthermore, Arthur M. Stimson, another 
researcher at the laboratory and later director of its Division of Sci- 
entific Research, was attempting to duplicate and verify Fricks's re- 
search. Unfortunately, McCoy informed Fricks, although Stimson had 
seen the "intracorpuscular bugs" once under the microscope, he had 



io6 



Rocky Mountain Spotted Fever 



"not been able to find them since to show us." McCoy remained 
confident, however, that Fricks's work would soon be confirmed. 

It was, however, the pathological approach of Wolbach that would 
reveal definitively the etiology of spotted fever. As he continued his 
examination of guinea pig lesions and tick tissues, an entirely unan- 
ticipated phenomenon altered Wolbach's perception of the nature of 
the disease organism. By December 191 6 he was certain that he had 
seen the organism multiplying "in the nuclei of the Malpighian tubules 
of ticks. This is the first instance known," he wrote to Cooley, "of a 
parasite multiplying inside of nuclei. As you see, I am getting away 
from the idea that the organism is a bacterium." 

In the spring of 19 17, Wolbach was finally able come to Montana 
for several weeks, where he conducted two autopsies on spotted fever 
victims. To his surprise, the lesions of the disease in humans had an 
"exact similarity" to those in animals. Commenting on this "remark- 
able feature," of spotted fever, Wolbach asserted, "There is probably 
no other disease of man which is so accurately duplicated in animals." 

In 19 1 8, Wolbach published a third preliminary report, this one on 
spotted fever in humans. In this paper, and in his report to the chairmen 
of the Montana state boards of health and entomology, Wolbach stated 
emphatically, "It is possible now to define Rocky Mountain Spotted 
Fever as a disease of the peripheral blood vessels, a specific endangiitis 
caused by the minute parasite described in my first report." Moreover, 
Wolbach had decided that the spotted fever organism was indeed 
unique. "My opinion regarding the organism," he wrote Cooley, "is 
that it represents a wholly new type of micro-organism and that it 
probably stands intermediate between the bacteria and protozoa as 
does spirochaeta."^^ 

Because of this intellectually exciting discovery, Wolbach hoped to 
launch a large-scale research project on spotted fever at Harvard. He 
invited Ralph R. Parker, who had investigated tick anatomy at Harvard 
for a brief period in 19 17, to assist with entomological studies for 
"one or two years" under a special grant from the university — an offer 
that appeared hard to turn down in Parker's mind. World War I and 
the 19 1 8 influenza pandemic, however, thwarted these plans. Wolbach 
dropped spotted fever work for a time in order to study influenza. He 
wrote to Cooley: "Some day and as soon as possible we shall see an 
adequately organized research on Spotted Fever; but that can not be 
until the war is over. We are stripped to the last man here and the 
calls for men are so urgent that it will be impossible to put through 
my intention now."^^ 

During that tumultuous summer, a tragedy in Noguchi's laboratory 



A Wholly New Type of Microorganism 



107 



at the Rockefeller Institute helped to confirm that Wolbach's organism 
was indeed the cause of spotted fever. Noguchi had been hospitalized 
in May 19 17 with typhoid fever and had suffered relapses that pre- 
vented his return to the laboratory for nearly a year. During his absence, 
all of Noguchi's cultures were maintained by his laboratory assistant, 
twenty-three-year-old Stephen Mohnscek. Shortly after Noguchi's re- 
turn to the laboratory in March 19 18, Molinscek fell ill. Noguchi later 
contended that Molinscek had scratched his hand or arm with a needle, 
but Molinscek told his attending physician that he could not remember 
any laboratory accident. On 18 March, Molinscek was hospitalized 
after developing symptoms that were provisionally diagnosed as Brill's 
disease, spotted fever, or possibly typhoid. ^° 

Noguchi himself cultured Molinscek's blood to rule out a laboratory 
spirochetal infection. Typhoid was also eliminated after several Widal 
tests gave negative results. When Molinscek died a week later, however, 
the diagnosis was still uncertain. Samples of Molinscek's tissues were 
sent to Wolbach at Harvard for examination, and he confirmed typical 
spotted fever organisms in the vascular lesions. Guinea pigs inoculated 
with Molinscek's blood showed characteristic spotted fever signs, 
hence the attending physician concluded that spotted fever had been 
the cause. 

By accepting Wolbach's diagnosis of Molinscek's terminal illness, 
the Rockefeller Institute in effect confirmed Wolbach's research. Fol- 
lowing this incident, the Harvard pathologist prepared a definitive 
paper on Rocky Mountain spotted fever that occupied the entire 197 
pages of the November 19 19 issue of the Journal of Medical Research. 
In addition to presenting an exhaustive review of the Hterature, clinical 
observations, epidemiological evidence, an analysis of the Hfe cycle of 
the tick vector, and a detailed description of his histological method, 
Wolbach expanded his discussion of the differences he had observed 
between the spotted fever organism and bacteria. He particularly em- 
phasized the fact that the organism invaded the nuclei of tick cells, 
often "completely filling and even distending the nucleus." Noting his 
early reluctance to accept the intranuclear bodies as forms of the 
spotted fever organism, Wolbach emphasized that he now regarded 
them "as the most characteristic form in infected ticks." He reiterated, 
moreover, that this phenomenon was the impetus for concluding that 
the agent of spotted fever indeed represented "a new form of micro- 
organism." He proposed that it be called Dermacentroxenus rickettsi, 
taking the genus name from the tick known to carry the disease and 
choosing the species name "in honor of Ricketts who first saw it in 
the blood."^^ 



io8 



Rocky Mountain Spotted Fever 



S. Burt Wolbach's drawing of the 
spotted fever organism in the 
tissues of infected animals. 
Wolbach's name for the organism, 
Dermacentroxenus rickettsi, was 
later supplanted by the currently 
accepted designation, Rickettsia 
rickettsii. (Reproduced from S. Burt 
Wolbach, "Studies on Rocky 
Mountain Spotted Fever," Journal 
of Medical Research 41 [19 19]: 
1-197.) 

Wolbach did not accept Ricketts's description of nonpathogenic 
organisms in the eggs of uninfected ticks. Robert A. Cooley prepared 
slides of noninfective tick eggs for Wolbach and identified short rods 
as identical with those that Ricketts had described. These short rods, 
Wolbach maintained, were not the spotted fever organism, which in 
tick eggs exhibited a lanceolate form. Ricketts had been misled, Wol- 
bach concluded, by having the "misfortune" to work with ticks con- 
taminated with the rod-shaped bacteria as well as with the spotted 
fever organism. Later researchers, however, confirmed Ricketts's 
finding of nonpathogenic rickettsiae in many noninfective ticks. 

Between 19 16, when Wolbach wrote his first preliminary report, 
and 19 1 9, when he pubHshed the comprehensive study, he apparently 
resolved his questions about the different coloration Ricketts had ob- 
served and described. Control of acidity in laboratory studies was not 
well understood before 1920, and, as Edmund V. Cowdry at the Rock- 
efeller Institute noted, by varying the composition of Giemsa's stain, 
either the red or the blue coloration could be enhanced. "The frequently 
noted tendency to be colored less intensely than ordinary bacteria with 
Giemsa's stain," Cowdry observed, was also difficult to estimate quan- 
titatively and varied "within wide limits."^"^ Because of this, it is im- 
possible to ascertain whether the organism described by Lunsford D. 
Pricks— despite his repeated protestations to the contrary— was iden- 
tical to Wolbach's. After 19 17, when Pricks was assigned to malaria 
control operations in Tennessee, he made no more effort to defend the 
organism he had identified." 




A Wholly New Type of Microorganism 



109 



In addition to the difficulty of identifying the spotted fever organism 
under the microscope, the riddle of its relationship to typhus — the 
disease it most closely resembled— likewise remained unsolved. Al- 
though the louse-borne nature of typhus had already been firmly es- 
tabhshed, its microbial etiology remained shrouded in mystery. In 
19 14, Harry Plotz and his colleagues in the Department of Pathology, 
Mount Sinai Hospital, New York, identified a Gram-positive bacillus 
associated with the blood of typhus fever victims and typhus-infected 
lice. They argued that this bacillus might play an important causative 
role in the disease. Two years later, a Brazilian researcher, Henrique 
da Rocha Lima, described red staining, "bluntly elliptical, olive- 
shaped" organisms "somewhat smaller than the smallest bacteria," 
which had the ability to penetrate the digestive tract cells of lice and 
there to multiply rapidly. Like spotted fever, these presumed typhus 
organisms resisted all efforts at cultivation. Even so, da Rocha Lima 
maintained that they were the etiological agents of typhus, and he 
named them Rickettsia prowazeki in honor of Ricketts and of the 
Polish investigator Stanislaus von Prowazek, both martyrs in typhus 
research. 

Wolbach, however, decUned to classify the spotted fever organism 
with that of typhus. In arguing for two different genus names, he noted 
that Ricketts's descriptions of the typhus and spotted fever organisms 
had been "markedly different."-^^ Wolbach's name, Dermacentroxenus 
rickettsi, was to stand as the designation for the spotted fever organism 
for more than two decades as he and other researchers investigated a 
variety of so-called Rickettsia-bodies and their connection to what 
came to be called the typhus-Hke diseases. Between 19 10 and 1930 
reports began to be published from nearly every continent about dis- 
eases exhibiting a high fever and rash, usually occurring after a tick, 
mite, or insect bite. Although the geographical isolation of most of 
these diseases precluded intensive laboratory study, they added an- 
ecdotal evidence that these were indeed a distinct class of diseases. 

In 19 10, Alfred Conor of the Pasteur Institute in Tunis reported 
with a colleague on a peculiar eruptive fever in Tunisia. Clearly different 
from known Mediterranean fevers, this malady caused a rash that was 
"difficult to classify in the nosological framework of skin diseases." 
Although the lesions, which appeared "first on the abdomen, then on 
the whole surface of the body, including the face," were not "spots 
or stains or pimples," Conor believed that the best description for 
them was "pimply lesions." This designation, he admitted, might "lack 
precision," but for want of a more explicit term, it appeared most 



no 



Rocky Mountain Spotted Fever 



useful. Many patients ill with the disease were observed to have bites, 
but these were attributed to "small mosquitoes," and tick bites were 
never mentioned. 

The same year, an American physician, Nathan E. Brill, described 
an unknown disease he had studied in 221 patients for more than a 
decade. In 1898, Brill had reported on apparent typhoid cases that 
produced no Widal reaction and displayed symptoms of typhus fever. 
Having pursued this mysterious fever for so many years. Brill con- 
vincingly demonstrated that it was a distinct, previously undescribed 
disease. No arthropods of any type were connected with this illness, 
but because of the thoroughness with which Brill presented his case, 
"Brill's disease" immediately attracted the attention of the research 
community and became a catch all for unknown, typhus-like symp- 
toms. 

European researchers at colonial stations in Africa also enriched the 
literature by describing a typhus-Hke disease in southern Africa. In 
191 1, Jose F. Sant'Anna reported in Parasitology that he had seen six 
patients in Louren^o Marques, in Portuguese East Africa, who suffered 
headache, joint pains, lymph gland inflammation, and a slight papular 
eruption on the fourth or fifth day. These symptoms occurred after 
the victims were exposed to the bites of larval ticks, which were so 
numerous in the grass of Louren^o Marques "as to constitute a ver- 
itable scourge." Identified primarily as Amblyomma hebraeum larvae, 
the ticks were especially prevalent in July and August. Because cases 
occurred infrequently and victims recovered spontaneously, few hos- 
pitals had experience with the disease. 

Sant' Anna's report stimulated G. H. F. Nuttall, the editor of Par- 
asitology^ to report his own correspondence about tick-borne fevers 
in southern Africa. A Johannesburg physician, G. E. Turner, Nuttall 
stated, had identified similar cases resulting from the bite of Am- 
blyomma hebraeum ticks. Turner described at the site of the tick bite 
"a kind of bleb over the bite," from which some "watery material" 
could be squeezed out, after which a small sore formed. Later, this 
lesion would be known as the tdche noire, or eschar, of the disease. 
Victims, Turner observed, were usually new arrivals to the area, for 
local inhabitants seemingly had immunity. C. W. Howard, an ento- 
mologist in Lourengo Marques, also reported additional cases. Howard 
recounted his own bout with the fever, which had occurred "some 
years ago," just after his arrival and following a tick bite. He also 
noted that the well-known researchers Edward Hindle and Frederick 
Breinl had contracted a similar fever at Runcorn Research Labora- 
tories, near Liverpool, while they were studying Amblyomma he- 



A Wholly New Type of Microorganism 



III 



braeum larvae sent from Capetown. Because all of these cases were 
presumably connected to the bite of a tick, Nuttall proposed that the 
African diseases be called tick-bite fever in order to distinguish them 
from the more general name, tick fever, which, he maintained, was 
closely identified with Rocky Mountain spotted fever and with re- 
lapsing fever.^^ 

J. G. McNaught, a member of the Royal Army Medical Corps in 
South Africa, held a different position about this unknown African 
fever. In a paper delivered to the South African Medical Congress in 
191 1, McNaught sought to distinguish it from paratyphoid fever, with 
which it had been confused. Although chnical symptoms in cases seen 
by McNaught were virtually identical to Nuttall's tick-bite fever, 
McNaught had observed tick bites in only a few cases and had been 
unable to find any "blood parasites" in blood smears. Having just read 
Nathan Brill's paper, moreover, McNaught argued that the unknown 
diseases in South Africa must be the same disease because of their 
clinical similarity.^^ 

In 19 1 7, J. W. D. Megaw of the Indian Medical Service added a 
new disease to the growing list by describing his own encounter with 
a fever contracted after a tick bite near Lucknow in the Kumaon Hills 
of the Himalayas. Quoting from the 19 13 unpublished report of a 
colleague about a disease identified as typhus in the same vicinity, 
Megaw determined that his illness was identical. He maintained, how- 
ever, that this disease was not typhus but rather a disease similar to 
Brill's disease. He argued, in fact, that all the typhus-like diseases with 
the exception of typhus itself should provisionally be classified as Brill's 
disease. The etiological agent, he speculated, was "probably an invisible 
virus," which was likely to have been "conveyed from man to man 
or from another animal to man by a biting insect or tick."^^ 

In the Far East, typhus-like fevers were reported from the Federated 
Malay States, Australia, and Japan. Although knowledge about those 
in Australia and the Malay States was Hmited to clinical descriptions, 
the disease known for centuries in Asia and called tsutsugamushi in 
Japan was subjected to closer scientific scrutiny.^^ In 18 10, Hakuju 
Hashimoto described a tsutsuga, meaning "disease," along the trib- 
utaries of the Shinano River. A similar disease, thought to be carried 
by mites, or mushi in Japanese, had been known at least since the 
sixteenth century in southern China. Laboratory investigations of tsut- 
sugamushi began in Japan in the early 1890s when it captured the 
attention of Shiramiro Kitasato, who returned from his work with 
Robert Koch in Germany to found the Institute for Infectious Diseases 
in Tokyo. Maintaining that the bite of a red mite transmitted the 



112 



Rocky Mountain Spotted Fever 



disease, Kitasato believed that he had seen a protozoan body in the 
red blood cells of patients. This theory gained support from the dis- 
tinguished Tokyo physician Masaki Ogata, himself a specialist in pro- 
tozoa. Many of Kitasato's colleagues at the Institute for Infectious 
Diseases, however, favored a theory of bacterial causation. A third 
theory held that tsutsugamushi was the result of a toxin contained in 
the body of the red mite. In 1908, U.S. Army surgeons Percy M. 
Ashburn and Charles F. Craig, who had confirmed Charles Wardell 
Stiles's findings that a protozoan organism was not the etiological 
agent of Rocky Mountain spotted fever, conducted a comparative study 
of spotted fever and tsutsugamushi. Although they noted these different 
theories, they concluded only that tsutsugamushi and spotted fever 
were distinct disease entities. 

Completing the group of typhus-like diseases known during the first 
two decades of the twentieth century was yet another, newly discovered 
during World War I. Known by various names, including Wolhynian 
fever, quintan fever, Polish fever, Meuse fever, and Russian intermittent 
fever, the descriptive appellation given to the disease by the British 
armies in northern France seemed most appropriate: trench fever. This 
disease never killed, but it caused much misery and loss of manpower 
in all the warring armies. Studies by several commissions, including 
one sponsored by the American Red Cross, showed that trench fever 
was a member of the typhus family, clinically characterized by head- 
ache, joint and muscle pains, a high fever, and a rash. Half the cases 
suffered relapses after the first bout.^^ 

The Great War of 19 14-18 in Europe provided the stimulus for 
further intensive research on epidemic typhus itself. Although typhus 
did not harass the armies of western European nations, it did ravage 
those of Russia, Serbia, and Poland. After the war ended, it settled 
with vengeance on Polish civilians. During the 19 15 Serbian epidemic, 
it was reported that every fifth man in the army was ill, and 135,000 
died. The Soviet revolution, which ended the war in Russia, did not 
bring relief from this malady. Between 19 19 and 1922, more than 10 
million cases of typhus were reported. Known to be a disease of cold 
climates and the winter months, typhus spread rapidly via its louse 
vector in the fur-lined clothing common in northeastern Europe. 

In 1919, S. Burt Wolbach was invited by Richard P. Strong, medical 
director of the League of Red Cross Societies, to head a commission 
to study typhus in Poland. Since Ralph R. Parker's 19 17 work on 
the anatomy of the tick had proven useful, Wolbach invited Parker to 
accompany the group for entomological studies on lice. After some 
discussion, the Montana State Board of Entomology approved Parker's 



A Wholly New Type of Microorganism 



113 



participation. Unfortunately, after Parker had traveled to Massachu- 
setts to join the group, he was stricken with a respiratory illness com- 
plicated by heart problems and was unable to make the journey/° An 
entomologist from the Lister Institute, Arthur W. Bacot, replaced 
Parker, but shortly after arriving in Poland, Bacot became ill with 
trench fever and had to return to England. "We seemed to be doomed 
to disappointment with entomologists," Wolbach wrote in frustra- 
tion.^i 

The work of the commission, therefore, focused primarily on "a 
minute histo-pathological study" of typhus lesions in humans and in 
hce. This was necessary, Wolbach maintained, in order to understand 
typhus as a disease, and particularly "for appraising relationships 
between lesions found and presumptive etiological agents which might 
be encountered." Bacteriological methods, he noted, were deliberately 
given second importance, "pending the development of indications 
during the research.""^^ In his 19 19 paper on Rocky Mountain spotted 
fever, Wolbach had noted the arguments surrounding da Rocha Lima's 
claim that Rickettsia prowazeki was the cause of typhus. The Brazilian 
had not demonstrated the organism in vascular lesions of typhus pa- 
tients, and such a demonstration, Wolbach believed, "would do much 
to settle the question." And indeed, the Red Cross typhus commission 
seemed to produce an irrefutable confirmation of da Rocha Lima's 
findings. "We conclude," Wolbach wrote in the commission's report, 
"that Rickettsia prowazeki is the cause of typhus." They had found 
not only "the virus of typhus and Rickettsia prowazeki'' inseparable 
in infective lice, but also "bodies indistinguishable from Rickettsia 
prowazeki^ demonstrable with great regularity, in the lesions of typhus 
in man.'"^^ 

Wolbach also incorporated into the commission's report a summary 
of knowledge about Rickettsia-bodies. Although he observed that "a 
satisfactory definition of rickettsia is not possible at present," it was 
possible to note the properties that the organisms held in common. 
They all had a bacterium like morphology but were smaller than 
bacteria. The difficulty of staining them with solutions used for bacteria 
was "a striking feature," as was "the failure to retain the stain by 
Gram's method." There were no motile forms. None of the rickettsiae 
pathogenic for humans had been successfully cultured. All had ar- 
thropod hosts, were highly specific for that host, and, except for typhus, 
were transmitted through the eggs of the female arthropod."^"^ 

No general acquiescence to the view that Rickettsia-bodies repre- 
sented a new form of microorganism, however, was forthcoming from 
the worldwide scientific community. Julius Schwalbe, Berlin corre- 



114 



Rocky Mountain Spotted Fever 



spondent for the Journal of the American Medical Association^ re- 
marked in June 192 1 that, despite numerous investigations on the 
etiology of typhus, there was still no common agreement. Because 
Rickettsia-bodies had not been cultured on artificial media, many re- 
searchers continued to reject them as the etiological agents of the 
typhus-like diseases and to support instead bacterial, protozoan, or 
viral etiologies. In 1920, for instance, a Brazihan researcher claimed 
that typhus was caused by a protozoan organism of the Herpetomanas 
genus, a group that he regarded as "piroplasms in a farther advanced 
stage of evolution.'"^^ The Piroplasma genus to which he referred, of 
course, was the one in which Wilson and Chowning had placed their 
presumed spotted fever organism. Two years later, another Brazilian 
claimed to have cultured a different typhus organism, which he de- 
scribed as a bacterium, on ascitic agar, a lifeless medium. H. M. 
Woodcock, a fellow at University College, London, preferred to dis- 
pense entirely with the concept of disease-causing Rickettsia-bodies. 
He argued that they were merely the end process of cell lysis and hence 
the cause of the typhus-like diseases was "an abnormal haemetabolic 
enzyme." In 1921, Harry Plotz's colleagues in New York compared 
Plotz's bacillus with Rickettsia-bodies and determined only that they 
were different. They withheld judgment on the precise relationship 
between typhus and either organism. Not even discussing Wolbach's 
claim that Rickettsia-bodies were unique organisms, they focused only 
on the bacterial or protozoan nature of the organisms, concluding that 
the evidence remained insufficient to classify them as either."^^ 

One red herring that complicated the picture further emerged from 
the 19 1 6 discovery of Viennese physician Edmund Weil and his English 
associate Arthur Felix that a strain of Bacillus proteus was agglutinated 
by the sera of typhus patients. Weil and Felix subsequently identified 
other strains of B. proteus and numbered them sequentially as X-i, 
X-2, etcetera. They also introduced terms to designate the motility of 
the organisms: O organisms were nonmotile while H organisms were 
motile. Their work showed that the O or nonmotile B. proteus or- 
ganisms agglutinated more specifically than did the H organisms. Of 
all the strains they isolated, OX- 19 gave the best results. 

What Weil and Felix had developed was the first serological test for 
typhus, which quickly became known as the Weil-Felix reaction. In 
1922, W. J. Wilson confirmed in the Lancet that "although the nature 
of the specific etiologic agent in typhus is still uncertain, and although 
no simple laboratory test apart from animal experimentation is yet 
available for its recognition," the Weil-Felix test using OX- 19 provided 
a specific laboratory diagnostic tool for confirming cfinical diagnosis. 



A Wholly New Type of Microorganism 115 

In 1921, moreover, a new strain of B. proteus was identified by A. N. 
Kingsbury, an Englishman. It appeared to be a modification of OX- 
19 with distinct antigenic differences. Called the OX-K strain after 
Kingsbury, it agglutinated sera of tsutsugamushi patients in low di- 
lution and that of victims of the typhus-like disease of Malaya — later 
shown to be an antigenic variant of tsutsugamushi — in high dilution.^*^ 

Although subsequent studies revealed that the Weil-Felix reaction 
was caused by a chance antigenic "fit" between the B. proteus and 
the typhus organism, a few bacteriologists declared that this bacillus 
was the "exciting organism" of typhus. It was soon demonstrated, 
however, that B. proteus alone would not induce typhus. Other in- 
vestigators, including Felix himself, argued that B. proteus and the 
typhus virus were simply variants of the same organism. Another 
champion of this theory was Max H. Kuczynski of BerHn, whose 
assistant, Elisabeth Brandt, died of a laboratory-acquired Rocky 
Mountain spotted fever infection. Kuczynski claimed to have cultured 
a spotted fever variant of the B. proteus organism, but his experiments 
were never repHcated in other laboratories.^^ 

Finally, a few researchers, including the respected Europeans Fred- 
erick Breinl and Rudolf Weigl, maintained that filterable viruses were 
the actual agents of the typhus-like diseases. In this theory, Rickettsia- 
bodies were considered either coincidental or a variant form of the 
viral agent. The agents of spotted fever and typhus had been dem- 
onstrated to be unfilterable, but that of trench fever had been filtered 
by the American Trench Fever Commission. "Filterabifity," it should 
be noted, was one of two links among a variety of unidentified sub- 
microscopic agents of disease and was not an entirely precise term, 
since experimental conditions such as the type of filter and the pressures 
exerted could vary. The other link between these agents, of course, 
was their inabihty to be cultured on Hfeless media. 

Several investigators, including S. Burt Wolbach and Rockefeller 
Institute researcher Peter J. Olitsky, attempted to convince their sci- 
entific associates that Rickettsia-bodies, like the filterable viruses, were 
obligate intracellular parasites— that is, they multipHed only within 
living cells. Such pathogens, they argued, would have to be grown 
using the emerging method of tissue culture, and they experimented 
with various tissue and media combinations. Unfortunately, the crude 
tissue culture techniques then available did not support luxurious mul- 
tipHcation of rickettsial organisms. The limitations of technique im- 
peded a clear demonstration that Rickettsia-bodies required the pres- 
ence of living cells to multiply.^^ 

Although definitive proof eluded him, Wolbach continued to argue 



Rocky Mountain Spotted Fever 



that the unique characteristics of Rickettsia-bodies demanded modi- 
fication of Koch's postulates. Dismayed that many researchers adhered 
uncritically to the criteria established for bacterial diseases no matter 
what laboratory investigations revealed, Wolbach spoke out forcefully 
in a 1925 speech to the Nev^ York State Association of Pubhc Health 
Laboratories. 

I wish to emphasize and to insist on the importance of methods which may 
be employed in the face of failure to cultivate insect-borne microorganisms in 
artificial mediums. Properly conducted experiments in which the insect vector 
serves as culture tube, after natural or artificial introduction of the "virus," 
have yielded evidence fully as reliable and in my opinion less open to mis- 
construction than in vitro cultivation. I feel it to be a duty to challenge skep- 
ticism based on rigid adherence to Koch's postulates when dealing with insect- 
borne diseases. ... I do not know what to say to those who, in the face of 
the evidence I have assembled, may still insist that Rickettsia prowazeki is not 
the cause of typhus, but simply invariably accompanies the virus of typhus, 
particularly to those who assume, like Breinl and Weigl, that the virus of 
typhus in man may be in ultramicroscopic form. The same line of reasoning 
may be applied to all infectious agents, whether or not cultivated in test tubes. 

The controversy over the relationship of Rickettsia-bodies to disease 
was finally settled only as a consequence of developments in research 
on the filterable viruses. Wolbach himself had remarked as early as 
19 1 2 that "when our knowledge of filterable viruses is more complete, 
our conception of living matter will change considerably, and ... we 
shall cease to attempt to classify the filterable viruses as animal or 
plant."^^ His views were supported by many of the leaders of virus 
research, notably Thomas Rivers at the Rockefeller Institute and 
W. G. MacCuUum of Johns Hopkins University School of Medicine. 
At the 1925 meeting of the American Association for the Advancement 
of Science, for example, MacCullum observed that progress in viral 
research had been slow because "we still use blindly the methods of 
investigation worked out for bacteriology." He suggested that "totally 
different mediums" might be necessary for the cultivation of viruses 
in addition to a conception of their nature different from existing 
views. 

The concept of microbial pathogens as minute plants or animals, 
however, was slow to change. In a 1930 editorial, the Journal of the 
American Medical Association observed that viruses might merely be 
"unusually small or unusually flaccid bacteria or protozoa," a concept 
that "would not introduce any new factors into current pathologic 
theory." There were, however, bacteriologists who proposed a "non- 
microbic 'liquid life' " theory and botanists who entertained the hy- 
pothesis that viruses were "self-propagating toxins, enzymes, or 'mor- 



A Wholly New Type of Microorganism 



117 



bidic bions.' " Should either theory be correct, the Journal noted, "such 
transmissible biochemical perversion would necessitate radical revi- 
sions of present methods of research and clinical attack. "^^ 

In 1935 the need for such a radical revision in concept was proven 
when Wendell M. Stanley, a biochemist at the Rockefeller Institute, 
crystallized the tobacco mosaic virus. Stanley, who later won a Nobel 
prize for his work, viewed the virus as an "autocatalytic protein, which, 
for the present, may be assumed to require the presence of living cells 
for multiplication."^^ Before this revolutionary discovery, viral re- 
search had focused primarily on study of the infectious diseases caused 
by the submicroscopic agents. Subsequently, the techniques of the 
relatively new discipHne of biochemistry were employed in an intense 
period of study that revealed the nucleic acid and protein composition 
of viruses— findings that rekindled discussion about the definition of 
life itself.^^ 

By the late 1930s viruses were accepted as different entities from 
bacteria or protozoa, as was their property of multiplying only inside 
living cells. With this change in concept, the rigid adherence to Koch's 
postulates decried by Wolbach finally ceased to be a major barrier to 
proving etiology in viral and rickettsial diseases. Because of their com- 
mon characteristic of intracellular multipHcation, moreover, the viral 
and rickettsial diseases came to be thought of as one group. In 1939 
the papers from a symposium at the Harvard School of Public Health 
were pubUshed as the first in a long Hne of studies entitled Virus and 
Rickettsial Diseases.^^ 

By the time this conference was held, the diseases caused by the 
pathogenic Rickettsiae were termed rickettsial diseases more often than 
typhus-like diseases, although the etiology of many geographically 
isolated maladies in this group remained unclear. Wide usage of the 
lower-case r implied a general acceptance of the concept that these 
organisms were the etiological agents of a separate class of diseases. 
New laboratory techniques introduced in 1939— which will be dis- 
cussed in chapter 9— had also proved useful for the immunological 
typing of rickettsial diseases. With these methods human rickettsial 
diseases were classified into three groups: the typhus group, the Rocky 
Mountain spotted fever group, and the tsutsugamushi group. 

Because these organisms were so small and so difficult to study, 
their taxonomic classification remained fluid for some time. Da Rocha 
Lima's designation Rickettsia prowazeki was honored as the type spe- 
cies for the typhus organism, but in 1927 Emile Brumpt, a French 
parasitologist, challenged Wolbach's genus designation of the spotted 
fever organism, Dermacentroxenus. Brumpt contended that it should 



ii8 



Rocky Mountain Spotted Fever 



be classed in the genus Rickettsia with the rickettsi species designation 
being preserved. In 1936, Henry Pinkerton of the Department of Pa- 
thology at Harvard University School of Medicine observed that 
Brumpt had not considered the intranuclear location of the spotted 
fever organism nor "the important morphological differences between 
it and Rickettsia proivazeki.'" Thus Pinkerton supported the separate 
genus proposed by his mentor, Wolbach. In 1940, Cornelius B. Philip, 
an entomologist who had worked with Rocky Mountain spotted fever 
investigations in Montana and who was, at that time, on the staff of 
the Army Medical School in Washington, D.C., attempted to bring 
some order into rickettsial taxonomy. In a Mayo Foundation lecture, 
Philip proposed that Rickettsia be adopted as the genus name for all 
the pathogenic rickettsiae, with Dermacentroxenus retained as a sub- 
genus designation for the spotted fever organism. By the 1957 pub- 
lication of the seventh edition of Bergey's Manual of Determinative 
Bacteriology, the definitive reference work on bacteriology, Philip's 
taxonomic criteria had been accepted, as evidenced in his authorship 
of the section on rickettsiae. The editors of the Manual, moreover, 
had adopted an international convention of doubhng the final / of 
most species names. In this way the Rocky Mountain spotted fever 
organism received the name by which it is now called, Rickettsia 
rickettsii.^^ 

Although in 1921 such standardization had not been achieved, in- 
ternational research on the typhus-like diseases had provided inves- 
tigators with clues that would prove fruitful during the ensuing decade. 
Wolbach's emphasis on pathological study of the tissues in rickettsial 
diseases, for example, provided strong, if not universally accepted, 
evidence that a new type of microbe caused spotted fever and epidemic 
typhus. In the United States most investigators accepted Wolbach's 
findings and used his techniques to confirm cUnical diagnoses of rick- 
ettsial diseases at post-mortem. When the U.S. Public Health Service 
returned to the Bitterroot Valley in 1922 to cooperate with Montana 
state authorities in seeking a medical solution to the problem of Rocky 
Mountain spotted fever, Wolbach's research provided the theoretical 
basis on which the renewed investigations were conducted. 



Chapter Seven 



The Spencer-Parker 
Vaccine 

We must also keep in mind that discoveries are usually not made by one 
man alone, hut that many hrains and many hands are needed before a 
discovery is made for which one man receives the credit. 

Henry E. Sigerist, A History of Medicine 



By the early 1920s the etiological agent of Rocky Mountain spotted 
fever had been identified and tick control efforts had been implemented 
for ten years, yet the disease continued to claim many victims and 
affect living conditions in Montana's Bitterroot Valley. In 1921 case 
incidence cHmbed precipitously to eleven cases and eleven deaths— a 
100 percent mortahty rate. In some areas of the valley, land prices 
had dropped from $125 to $15 per acre. Potential income from tourism 
v^as likevs^ise threatened by the presence of the disease in the valley.^ 
Disturbed by these problems and unsatisfied With, the results of earlier 
control measures, local citizens clamored for additional federal assist- 
ance in attacking the problem. "A crisis has been reached in the Spotted 
Fever situation," w^rote the manager of the Missoula Chamber of Com- 
merce to W. F. Cogsv^ell, secretary of the Montana State Board of 
Health. "A greater number of deaths from this dreaded disease has 
occurred this year than in the past, despite the fact that the people 
generally are aw^are of the malady and take precautions against it. The 
people are aroused to a very emphatic desire that the United States 
Public Health Service take an active hand in the fight to overcome this 
disease."^ 

Exacerbating the situation w^as the laboratory-acquired spotted fever 
death of Arthur H. McCray, Montana's first full-time state bacteri- 
ologist. McCray had assumed the post in October 19 17 and had taken 
up spotted fever research during his spare time, hoping "to derive a 
curative serum for the treatment of the disease." In early June 1919, 
how^ever, w^hile working in the laboratory, he w^as infected. McCray 
died on 14 June 1919.^ 



119 



I20 



Rocky Mountain Spotted Fever 



As secretary of the state board of health and president of the state 
board of entomology, Cogswell wired the newly appointed surgeon 
general, Hugh S. Cumming, and appealed to the Montana delegation 
in Congress for assistance in persuading the U.S. Public Health Service 
to reenter the work. The surgeon general sent Thomas Parran, a rising 
Service administrator and later surgeon general himself, to evaluate 
the situation. Parran's visit was widely hailed in the Montana press 
as the beginning of renewed federal support for spotted fever research.^ 
Parran was unsure if future cooperative measures would be productive, 
because of past tensions between state and federal authorities over 
jurisdiction in tick control efforts. A meeting with local civic groups, 
however, convinced him that the general public in the valley seemed 
"to be awakened to the menace of this disease" and was "very anxious" 
for the Service to assist in its eradication.^ 

To emphasize the state's cooperative intentions, Cogswell obtained 
pledges of twenty-eight hundred dollars from Missoula civic clubs to 
defray initial expenses of the work, and he secured an abandoned 
school building near Hamilton to serve as a laboratory. The "sub- 
stantial, two story brick school building" that came to be known as 
the "schoolhouse lab" was located on the infected west side of the 
river about two miles from Hamilton.^ Its West Valley Road site in 
the river bottom area, however, was considered free from infected 
ticks. A consolidation of schools in Hamilton had left it empty. Luns- 
ford D. Fricks, who inspected the facihty at the request of the surgeon 
general, enthusiastically wrote; 

This new laboratory is a much more elaborate affair than any field laboratory 
which has been previously used in conducting spotted fever investigations. It 
is excellently lighted— kept well heated and has two sheds on the same school 
lot which can be used for storing automobiles and supplies. Dr. [Ralph R.] 
Parker has installed the necessary shelving, animal cages, and other equipment 
including laboratory animals. ... In addition to Dr. Parker there are at present 
five employees in the laboratory— three at $150 each per month and two, a 
clerk and janitor, at $90 each. These men have been employed in equipping 
the laboratory, making maps, caring for animals and the building, and will 
be ready to begin field investigations at any time the season permits.^ 

Such concrete efforts by Montana authorities proved convincing, 
hence on 4 March 1922, Cumming detailed to Montana Roscoe Roy 
Spencer, the young Passed Assistant Surgeon who in 191 5 had assisted 
Fricks in spotted fever work. The thirty-four-year-old Spencer was 
born in 1888 in West Point, Virginia, the last of five children of Branch 
Worsham Spencer and Emma Roy Burke Spencer. He took his A.B. 
degree in 1909 at Richmond University, and in 19 13 he received the 



The Spencer-Parker Vaccine 



121 




The sign over the door identifies this abandoned schoolhouse on the west 
side of the Bitterroot River as a U.S. PubUc Health Service Laboratory. 
Widely known in the 1920s as the "schoolhouse lab," this was the site 
where Roscoe R. Spencer and Ralph R. Parker ground up ticks to make a 
vaccine against spotted fever. (Courtesy of the Rocky Mountain 
Laboratories, NIAID.) 



M.D. degree from Johns Hopkins University School of Medicine. Be- 
lieving that he could "never assume a radiant bedside manner," Spencer 
joined the U.S. Public Health Service in 19 14 as an assistant in the 
Hygienic Laboratory and v^as commissioned an Assistant Surgeon later 
that year by President Woodrov^ Wilson. During his 191 5 work on 
spotted fever, Spencer had not been impressed by Fricks's research. 
After being recalled to Washington in the fall, Spencer assumed he 
w^ould have no further involvement v^ith the disease. For the next seven 
years, he completed the usual tour of duty stations, including plague 
control in Pensacola, Florida.^ 

Although Ralph R. Parker had been in charge of the board of en- 
tomology's work since 191 8, the Service insisted that Spencer be placed 
in charge of spotted fever investigations in 1922, "simply because," 
as Fricks explained to Cogswell, who had complained, "from a Service 
standpoint Dr. Spencer out-ranks Dr. Parker. This is a fixed rule in 



122 



Rocky Mountain Spotted Fever 



the Service, as you perhaps know, from which it would be impossible 
to deviate." Spencer, of course, was a physician, and Parker, an en- 
tomologist. The arrangement threatened to rekindle the old antagonism 
between the two groups, because Parker saw no reason to relinquish 
his position of authority. Cogswell, however, "had a talk" with Parker 
about the delicacy of the situation, soothing his injured ego with the 
assurance that Spencer "could come in no other capacity." Parker 
decided to accept the situation without further protest. When Spencer 
arrived, the two men amicably agreed that all publications about spot- 
ted fever would be joint.^ 

Initially, Spencer and Parker planned an ambitious program of field 
investigations that would be supplemented with laboratory studies as 
time permitted. Parker planned a broad study on the relationship that 
ecological factors— the distribution of vegetation, rodents, and ticks — 
might have to human disease and to one another. Believing that there 
was a natural cycle regulating spotted fever in nature, Parker especially 
wanted to continue his work on the links among rabbits, their ticks, 
and spotted fever. The field studies needed to implement such a 
program, however, were costly, time-consuming, and of questionable 
value to an improved tick control program. Fricks, who reviewed the 
plan for the Service, believed that sufficient investigational work had 
already been done to assure practical control through grazing restric- 
tions and rodent destruction. Spencer, too, soon lost his enthusiasm 
for Parker's wide-ranging entomological studies. For the moment, how- 
ever. Spencer let matters ride and concentrated on laboratory studies, 
hoping that a medical solution to the spotted fever problem might be 
found. 

Laboratory methods for identifying natural spotted fever infection 
in ticks had not changed significantly since Howard Taylor Ricketts 
identified the guinea pig as an experimental animal. Groups of suspect 
ticks were secured by a wire mesh collar on guinea pigs and allowed 
to engorge for several days, after which the animals were watched for 
symptoms of the disease. In Spencer's work with plague in Pensacola, 
however, fleas had been ground up and injected into the peritoneal 
cavities of guinea pigs, a method that shortened the waiting period by 
several days. Spencer suggested to Parker that they try the same method 
with ticks to test for spotted fever infection. Initially they allowed ticks 
to feed on infected animals for a time, after which they were ground 
up and injected into guinea pigs. This experiment worked well— five 
of the six pigs developed spotted fever. Continuing on this course, they 
separated 1,500 ticks into 102 lots, and, without allowing them to 
feed first, ground them up and inoculated them into guinea pigs. Sur- 



The Spencer-Parker Vaccine 



123 




The two "R.R.s" who developed the first vaccine effective against Rocky 
Mountain spotted fever: Roscoe R. Spencer, a physician in the U.S. Pubhc 
Health Service (left) and Ralph R. Parker, a Montana entomologist 
appointed as a Special Expert to the Service. When the vaccine had been 
demonstrated effective. Spencer returned to other Service assignments in 
Washington, D.C. Parker continued as director of the Rocky Mountain 
Laboratory until his death in 1949. (Courtesy of the National Library of 
Medicine and the Rocky Mountain Laboratories, NIAID.) 



prisingly, none of the animals developed spotted fever. Many proved 
immune to subsequent direct inoculations of known lethal doses. 

These results appeared to indicate that Spencer's new method was 
a failure. As Louis Pasteur observed, however, chance favors the pre- 
pared mind. No conclusion was drawn about the results of the ex- 
periments until Henry Cowan, a field assistant, killed a mountain goat 
and brought it into the laboratory because it carried many engorged 
ticks. These ticks, too, were emulsified and injected, and they un- 
questionably produced spotted fever in guinea pigs. Spencer and Parker 
simultaneously realized the significance of their findings. The only 
difference between the ticks that produced immunity and those that 
caused spotted fever was that the latter had already had a blood meal 



124 



Rocky Mountain Spotted Fever 



on an animal. A jubilant but cautious Spencer wrote of this insight 
and its potential implications to Surgeon General Hugh S. Gumming. 

One might be justified in inferring from these results that the virus in the tick 
. . . requires fresh animal blood to stimulate its growth and multiplication. 
There is good reason to believe that the inoculated ticks which conferred 
immunity would have produced fever if fed. In other words the virus needs 
to be primed with fresh animal blood before it can become infective. ... Up 
to the present time all attempts to attenuate the virus in vitro have met with 
failure but there appears now a possibility of attenuating it in the body of the 
tick over a long period of time." 

Before Spencer suggested the short cut of emulsifying and injecting 
ticks, no change in virulence of the spotted fever organism had been 
suspected. By altering the method, Spencer unintentionally introduced 
a new way of viewing the process. The resulting insight also explained 
two observations by earlier investigators. First, as Spencer noted: "this 
view fits in with the fact that a tick must be attached for some hours 
before it becomes infective. The very earliest time of infectivity as 
determined by Ricketts was 1V4 hours of feeding and 8 to 10 hours 
as an average." Second, it illuminated the origin of cases of spotted 
fever that had no history of tick bite. Spencer had already demonstrated 
that the internal organs of infected animals would communicate the 
disease when rubbed on shaved or scarified skin.^"^ Since engorged ticks 
contained highly virulent organisms, a person who had crushed such 
a tick might transfer the disease on the hands to any abrasion or cut 
in the skin. 

Once again, a fresh approach yielded results where previous inves- 
tigations had stalled. With his new insight. Spencer reviewed the earlier 
work of Ricketts and Fricks, in which each had produced immunity 
in guinea pigs by inoculating them with the eggs of infected ticks, and 
found it suggested promising avenues for research. Enthusiastically he 
wrote to Fricks, "These experiments of yours and Rickett's [sic] appear 
to me now highly significant." Observing that they had apparently 
attenuated the organism in tick eggs over time. Spencer predicted, "If 
I am correct in this assumption, it appears to me that in this direction 
lies the road to successful vaccination of people." 

Before more conclusive experiments could be undertaken, however, 
Spencer's observation about the potentially infectious nature of en- 
gorged ticks on abraded skin was confirmed in a tragic manner. William 
Edwin Gettinger, an undergraduate student at Montana State Agri- 
cultural College in Bozeman, had been hired at his "earnest request" 
as a student assistant for the summer. Born 16 July 1899 in Melrose, 
Iowa, Gettinger had studied entomology with Robert A. Gooley and 



The Spencer-Parker Vaccine 



125 



was saving money to attend medical school. After the serendipitous 
discovery in April, Gettinger assisted Spencer in dissecting ticks and 
making stain smears of their organs in order to test them for the 
presence of rickettsiae. Although never bitten by a tick, Gettinger 
apparently rubbed at a pimple on his neck repeatedly w^hile working 
in the laboratory. In late June he fell ill with typical spotted fever 
symptoms. It was a fulminating case, and the young man was soon 
delirious. Until he died on 30 June 1922, a few weeks before his twenty- 
third birthday, Gettinger "imagined himself in the laboratory and 
talked of it constantly." Gettinger's death brought to three the number 
of laboratory-acquired spotted fever cases in Montana and gave re- 
newed impetus to development of a successful vaccine. 

At the end of the summer. Spencer left the schoolhouse laboratory 
in Parker's care and returned to the Hygienic Laboratory in Wash- 
ington, D.C., to continue his experiments. Methodically he explored 
various properties of the spotted fever organism in light of the previous 
spring's discovery. Spencer demonstrated that spotted fever rickettsiae 
would remain infective in animal tissues if kept in 100 percent glycerine 
at a temperature constantly below — 10° C and that rickettsiae could 
readily be demonstrated in ticks after incubation or after feeding the 
ticks. 

Confident that laboratory work would soon provide medical inter- 
vention for the disease. Spencer apparently decided that his doubts 
about the cost and benefits of Parker's broad-ranging ecological studies 
were well founded. He therefore recommended that the control work 
be abolished or cut back severely. Spencer's memo, however, ran into 
trouble with Hygienic Laboratory director George McCoy and Surgeon 
General Hugh Gumming, both of whom rejected the recommendation. 
Although they gave no reason for their decision, it is likely that earlier 
battles between Service physicians and Montana entomologists con- 
vinced them that tolerance was preferable to confrontation.^^ 

At about this same time, Hideyo Noguchi at the Rockefeller Institute 
again became interested in the spotted fever problem. Proceeding along 
the older path of research investigated by Ricketts, Noguchi announced 
in November 1922 that he had developed an immune serum for treating 
a person infected with spotted fever. Instead of using horses, as Ricketts 
had, Noguchi produced his serum in rabbits, declaring that it was 
superior, "both in potency and quantity." In guinea pigs, Noguchi 
wrote, I cc of the serum suppressed a spotted fever infection if given 
within twenty-four hours of the tick bite. Noguchi argued that guinea 
pig and human susceptibility to the disease were comparable and 
recommended an immediate injection of about 16 cc for adults "in 



Rocky Mountain Spotted Fever 



every instance when the bite of a tick gives reason to suspect a possible 
infection with spotted fever." 

In Montana the news of Noguchi's serum was greeted with some 
skepticism. Remembering the abortive efforts of Ricketts and his col- 
leagues in a similar attempt, Cooley remarked, "I do not see that there 
is anything particularly new in . . . [the serum] excepting, perhaps, 
that he has figured out the minimum dosage for a guinea pig and 
computed the dosage for man." Nonetheless, state board of health 
secretary W. F. Cogswell wrote to Noguchi, requesting that he make 
his serum available for prophylactic purposes in Montana. It was 
doubtful that the serum could function as a vaccine, Noguchi replied, 
because, being a foreign protein, it would be quickly eliminated from 
the body. He suggested that instead it would be useful to give the 
serum to anyone bitten by an infected tick.^° 

During the next few months, Noguchi went one step farther and 
developed a prophylactic vaccine by adding infected guinea pig blood 
to the immune rabbit serum. This serovaccine gave full protection to 
guinea pigs. Because of the danger of using live virus, Noguchi studied 
the immunizing power of a heated vaccine. He concluded that heating 
the mixture to 56—60° C for twenty minutes did not destroy the im- 
munizing property, although it did "markedly" reduce it.^^ A decade 
before, Ricketts had pursued similar studies and abandoned them. 

Tick season in 1923 offered the first opportunity for Noguchi's 
serovaccine to be tested in humans. Since Noguchi planned to come 
to Montana for the tests, the Montana State Board of Health capitalized 
on his visit to further its longstanding goal of educating the public 
that spotted fever was a regional problem, not Hmited to Montana. 
In March 1923 the board issued a call to the state and local health 
officers of the Rocky Mountain region to meet on 5 and 6 April in 
Missoula to discuss the current status of Rocky Mountain spotted 
fever in their states. Noguchi would, of course, be present to discuss 
his new vaccine. S. Burt Wolbach was likewise invited, as were rep- 
resentatives of the U.S. Public Health Service. 

Papers were presented on a wide variety of subjects relating to 
spotted fever, but Noguchi's presence and announcement of a vaccine 
overshadowed all other concerns. Because of Noguchi's Japanese or- 
igins and connection with the prestigious Rockefeller Institute, the 
Montana press devoted nearly as much space to descriptions of the 
famous investigator as to information about the conference. "Intensely 
alive, intensely. Orientally poUte— and, most intensely, devoted to 
science and humanity. That is Doctor Noguchi," exclaimed one Mis- 
soula reporter. Under the banner headline "Spotted Fever Heroes," 



The Spencer-Parker Vaccine 



127 



another article noted that nine Japanese residents of Missoula had 
volunteered to take the first human injections of their countryman's 
vaccine.-^ 

Although the method of preparing the vaccine given to the Japanese 
volunteers was not described, Noguchi apparently was willing to risk 
administering the live virus mixture in order to achieve protection. 
This certainly seems to have been his plan when he offered the vaccine 
to members of the schoolhouse laboratory in Hamilton. In an oral 
histor}- memoir, Spencer recalled insisting that the vaccine be heated 
to 45° C in order to kill the rickettsiae. Noguchi reportedly opposed 
this move, but he eventually complied and vaccinated five members 
of the laboratory staff. Later, other Bitterroot Valley residents vol- 
unteered, bringing to 152 the total number of people who took No- 
guchi's serovaccme. A number of them became ill with serum sickness, 
possibly because the vaccine contained two t}-pes of foreign proteins — 
those in the rabbit serum and those in guinea pig blood. 

The real measure of the vaccine, of course, was whether it would 
prevent the disease or lessen its severity' if contracted. Initially there 
was an indication that it was efficacious. In July after he was vaccinated 
in April, Ralph R. Parker sustained a laboratory accident in which he 
knocked a syringe full of infected blood off a table. It stuck in his leg 
as it fell. "I didn't think anything of it for a few seconds," he wrote 
to Cooley, "and then it dawned on me what I had done." Parker 
immediately treated the wound with iodine and "burned it out" with 
nitric acid. "I am not worrying much. ... I think the vaccine is all 
right. ... I feel that there is no danger, but of course will feel uneasy 
for a few days."^-' Parker did not become ill, but w^hether the vaccine 
or luck protected him was unclear. 

A second case produced a different outcome. It occurred in George 
Michky, Jr., son of the laboratory's janitor.-^ The child had been 
vaccinated with Noguchi's vaccine, and although he recovered, he 
suffered a long illness. Widely publicized, the case cast doubt on the 
value of the vaccine. Noguchi maintained that one case proved very 
little but noted that he was attempting to develop a safe way to ad- 
minister the more potent unheated vaccine to humans. Spencer and 
Parker's immediate response to the Michky case was to make a large, 
painted sign, visible to all approaching the schoolhouse laboratory, 
warning them of the danger and advising them that they entered at 
their own risk.-' 

Noguchi discontinued his spotted fever research in November 1923, 
when he departed New York for Brazil and turned his attention to 
yellow fever. Upon his return in 1925 he resumed the work, searching 



128 



Rocky Mountain Spotted Fever 



for a way to produce a safe, potent, unheated serovaccine. Both Wol- 
bach and Parker viewed this work as promising, but Noguchi was 
unable to protect monkeys with the preparation, a step he beUeved 
essential before testing the vaccine on humans. Increasingly, he became 
preoccupied with identifying the causative organism of yellow fever. 
After asserting that a spirochete was the guilty organism, Noguchi 
found his work attacked by other researchers. In 1928 he traveled to 
Africa with hopes of vindicating his research, but instead he contracted 
yellow fever and died.^^ 

Because of the inconclusive results obtained with Noguchi's sero- 
vaccine, Roscoe R. Spencer pressed on with his own work after re- 
turning to the Hygienic Laboratory. During the fall and winter of 
1923-24, he continued to seek a means to attenuate the organism and 
produce a vaccine. By injecting guinea pigs with various dilutions of 
an emulsion made from the engorged ticks, he determined that 1/5,000 
of a tick would cause infection in a guinea pig. He refined his previous 
experiments on the virulence of the spotted fever organism in hiber- 
nating, warmed, and engorged ticks. He determined that the organism 
in tick tissues was unfilterable, a point not examined by Ricketts and 
Wolbach before him. Curiously, Spencer found that rickettsiae could 
not be demonstrated in some infective ticks. Subsequent studies threw 
no additional Hght on this problem. 

Even with much new information. Spencer could identify no method 
for translating it into a usable vaccine. The key that unlocked the 
puzzle came from a Czechoslovakian researcher working in Austria 
on a vaccine for typhus, spotted fever's closest rickettsial relative. 
Worldwide work on the typhus-like diseases was abstracted in several 
journals, including the Journal of the American Medical Association, 
and through these summaries Spencer kept abreast of each new de- 
velopment. In February 1924 he spotted the Journal's abstract of an 
article originally published by Frederick Breinl in the Journal of In- 
fectious Diseases. Instead of attempting to make a typhus vaccine using 
the standard tactic of mixing typhus organisms in blood with immune 
serum, Breinl demonstrated that rabbits were actively immunized "by 
injecting emulsified louse intestines, to which phenol has been added." 
Protection was achieved, he speculated, because of the immunizing 
properties of quantities of dead typhus organisms present before the 
phenol was added. 

Spencer seized upon Breinl's method, even though he concluded that 
Breinl's explanation of how immunity was produced was not applicable 
to spotted fever. As soon as he returned to Montana in late February 
1924, Spencer prepared a vaccine from infected ticks. From his ex- 



The Spencer-Parker Vaccine 



129 



periments on changes in spotted fever virulence in fasting and engorged 
ticks, Spencer knew he needed to use fully engorged ticks to obtain a 
vaccine that w^ould maximize protective value. Using a mortar and 
pestle, he ground up the ticks in a salt solution to which 0.5 percent 
phenol had been added to kill the rickettsiae. Each i cc dose contained 
the equivalent of one tick, and since he had determined the minimum 
infectious dose to be 1/5,000 of a tick, each guinea pig received 5,000 
infectious doses of killed vaccine in the injection. In every guinea pig 
so inoculated, the vaccine prevented illness w^hen the animal was in- 
jected with infectious spotted fever blood fourteen days later.^^ 

By May, Spencer had sufficient confidence in the vaccine to inoculate 
himself with it. Although it caused no adverse reaction, Parker and 
the rest of the staff remained wary of taking the vaccine until further 
tests had been conducted. There was certainly reason for caution. 
Preparing a human vaccine from an arthropod vector had never before 
been attempted. Breinl had protected animals from typhus, but his 
louse intestine vaccine had not been used on humans. Rabies vaccine, 
of course, was made from the dried spinal cords of infected rabbits 
and smallpox vaccine from the pus in cowpox scabs, hence the concept 
of utilizing animal tissues was not new. Noguchi's vaccine, containing 
two foreign proteins, however, had caused adverse reactions. Doubtless 
this memory dampened the staff's enthusiasm for an unproven vaccine 
containing tick proteins. 

Testing of the vaccine was delayed during the spring and summer 
of 1924 because of a newly identified illness among laboratory workers. 
Shortly after Spencer arrived in Montana, Parker queried him about 
pecuHar lesions observed in the laboratory's rabbits. Spencer believed 
the lesions were caused by tularemia, a disease with symptoms similar 
to bubonic plague. Tularemia had first been described in 191 1 by the 
Hygienic Laboratory's director, George W. McCoy, as a plague-like 
disease of rodents, which he had found while doing research on plague 
in Tulare County, California. He named the disease after this location. 
Another Hygienic Laboratory researcher, Edward Francis, had become 
an expert on tularemia, demonstrating that humans could be infected 
through handling infected rabbits or through the bites of infected ticks, 
deer flies, and other arthropods. Spencer thus wrote to Francis about 
his suspicions, and the senior man confirmed the diagnosis. The dis- 
covery of tularemia in laboratory animals stimulated the staff of the 
Hamilton laboratory to expand their studies into a second tick-borne 
disease. More important to the spotted fever work, however, was the 
highly contagious nature of tularemia. In July, Spencer and Sam Ma- 
clay, an assistant bacteriologist, came down with the disease. Both 



130 



Rocky Mountain Spotted Fever 



recovered, but Spencer was quite ill for several w^eeks. After Spencer 
returned east, Parker himself contracted the disease and w^as ill for 
seven v^eeks.^^ 

During Parker's bout with tularemia, George Henry Cowan con- 
tracted spotted fever. The son of Bitterroot Valley pioneers. Cowan 
had the longest continuous record in the state in spotted fever research. 
He had begun working for the U.S. Bureau of Entomology in 19 13, 
and his exemplary record had earned him a promotion in 19 17 to 
chief deputy in tick control work under the Montana State Board of 
Entomology. When the U.S. Public Health Service took over the work 
in 19 21, Cowan had been made a field assistant. His duties included 
making rough maps in the field, trapping experimental animals, and 
collecting ticks from animals and special localities. 

Because Cowan had escaped spotted fever despite a decade of dan- 
gerous work, one Montana newspaper speculated that, "as many other 
natives have done, he perhaps came to regard himself as immune" to 
the disease. He apparently contracted spotted fever in the laboratory 
through handling infected material, for there was no evidence of a tick 
bite. As the thirty-eight-year-old man became sicker, his physician 
administered some of Spencer's vaccine in hope that it might have a 
therapeutic effect. This effort was in vain: Cowan died on 29 October 
1924. Parker wired Spencer about Cowan's death and in the same 
telegram requested enough vaccine to inoculate the laboratory staff.^^ 

During the winter of 1924-25, Spencer tested his vaccine on mon- 
keys as well as on guinea pigs. Monkeys provided an animal model 
so much closer to humans that Hideyo Noguchi had written to Spencer, 
"If you can protect Macacus rhesus with your vaccine, I shall be 
convinced that it will protect man." Spencer inoculated eight monkeys 
with his vaccine, leaving five others unvaccinated as controls. An im- 
munity test two weeks later produced frank spotted fever in the con- 
trols, but all of the vaccinated monkeys remained healthy. He also 
tested for evidence of human antibodies to the vaccine by injecting 
guinea pigs with combinations of serum from vaccinated persons and 
infective blood serum. These results indicated that the vaccine did 
indeed produce antibodies to spotted fever.^^ 

When Spencer returned to Montana in the spring of 1925, enough 
vaccine was prepared to vaccinate thirty-four people in the Bitterroot 
Valley— primarily laboratory and field staff and other residents whose 
occupations exposed them to spotted fever infection. Since human 
dosage had not been worked out precisely, the vaccine was adminis- 
tered in two to four doses of i or 2 cc at five-day intervals. No severe 
reactions were encountered, but most people reported local redness. 



The Spencer-Parker Vaccine 




During the effort to develop a 
vaccine against spotted fever, 
three w^orkers at the schoolhouse 
laboratory became martyrs to lab- 
orator>'-acquired infections. Wil- 
liam Edwin Gettinger (top left), a 
student assistant with the U.S. 
Public Health Service, died in 
1922; George Henry Cowan (bot- 
tom), a field assistant with the 
Montana State Board of Entomol- 
ogy and the U.S. Public Health 
Service, in 1924; and Albert 
LeRoy Kerlee (top right), also a 
student assistant to the Service, in 
1928. (Courtesy of the Rocky 
Mountain Laboratories, NIAID.) 




132 



Rocky Mountain Spotted Fever 



swelling, and heat for two days around the site of the injection. A few 
also suffered headaches and muscular pains. One recipient observed 
that his "hand became swollen and the arm was somewhat uncom- 
fortable for a while," but that he was able to continue his regularly 
scheduled activities. "I imagine that it looked worse than it felt," he 
commented.^^ 

The first test of the vaccine's effectiveness came unexpectedly in 
April, when E. O. Everson, a forty-three-year-old employee of the 
Montana State Board of Entomology, contracted spotted fever. He 
had actively sought vaccination because he dipped tick-infected cattle 
and often picked engorged ticks off by hand. The course of his illness 
was mild, and although convalescence was prolonged, he recovered. 
Spencer noted that it was impossible to state without reservation "that 
the vaccine modified the course and severity of the infection." Four 
unvaccinated victims of spotted fever that spring, however, died within 
ten days, and since the disease in persons over forty was nearly always 
fatal, Everson's recovery augured well.^^ 

The apparent success of the vaccine on a small scale produced a 
large demand for it the following year, even though it remained an 
experimental product. Spencer underwent surgery for appendicitis in 
March 1926 and was unable to return to Montana, but Parker and 
his staff produced enough vaccine to inoculate over four hundred 
persons, ranging in age from four to seventy, in the Bitterroot Valley 
and in Idaho. In the southern valley town of Darby, school was dis- 
missed in order to allow people to be vaccinated. Each person received 
2 cc of vaccine in each of two injections one week apart. Few severe 
reactions to the injections occurred; none was fatal.^^ 

Ralph R. Parker and L. B. Byington, whom the U.S. Public Health 
Service had detailed to Montana in Spencer's place, were equally in- 
terested in analyzing the vaccine's effectiveness against the mild Idaho 
form of spotted fever. A large concentration of Basque sheepherders, 
whose occupation rendered them particularly vulnerable to spotted 
fever, provided an ideal population for a trial of the vaccine in Idaho. 
Since infection often took place on the range far from medical assis- 
tance, the incapacitation of a sheepherder often meant loss of many 
sheep to the owners. Idaho stock owners thus urged their sheepherders 
to take the vaccine. Because some resisted and, in any case, there was 
insufficient vaccine to inoculate all of them, those not vaccinated served 
as controls in studying the new product's effectiveness. None of the 
94 sheepherders vaccinated in 1926 developed spotted fever, while 
thirteen cases occurred among 180 who had not been vaccinated. When 
this test was repeated in 1927, one case occurred among 99 vaccinated 



The Spencer-Parker Vaccine 



133 



men as opposed to nine cases among 184 controls.'^^ 

Three cases of spotted fever at the laboratory further increased 
confidence in the vaccine's value. Two young vaccinated laboratory 
attendants, Martin Nolan and Frank P. Merritt, suffered only mild 
bouts with the disease. When the sixty-two-year-old janitor, Alex Chaf- 
fin, fell ill, the vaccine's protective power was demonstrated most 
impressively. Parker observed that Chaffin's recovery was a first "for 
a man of his years" in the Bitterroot. "It is believed," Parker continued, 
"that these . . . cases place the value of the vaccine outside any realm 
of doubt."4i 

A four-year retrospective study of spotted fever in the Bitterroot 
later confirmed these empirical observations of the vaccine's efficacy. 
Spencer and Parker excluded the high-risk laboratory workers and 
examined the records of 1,208 residents of a known infected zone on 
the west side of the valley. Of these, 496 chose to be vaccinated, while 
712 refused and thereby served as controls in the study. Over the four- 
year period, only three cases of spotted fever occurred in vaccinated 
persons, and none was fatal. In contrast, nine cases occurred in the 
control group, seven— or 77.7 percent— of which were fatal. 

For the next fifteen years, Parker continued to gather extensive 
records from which he published data confirming the efficacy of the 
vaccine. Overall, vaccinated adults experienced a 74.24 percent lower 
fatality rate than did the unvaccinated. In Idaho, where the disease 
had never been virulent, the number of cases decreased markedly as 
the number of vaccinated persons increased. Scientific objectivity re- 
jected the obvious conclusion that the vaccine fully protected people, 
for, as Parker acknowledged, other factors such as ecological shifts 
that were not well understood could be responsible. Nonetheless, the 
partial correlation convinced most people of the vaccine's protective 
power and increased demand throughout the west."^^ 

Developing the best method to mass produce the vaccine involved 
a trial-and-error process. Parker worked with his chief technician, Earl 
W. Malone— who alone among all employees involved with the vac- 
cine-making process escaped spotted fever infection— to find a tech- 
nique that would yield a consistent level of protection in all lots. Initially 
they made the vaccine in the fall before its distribution in the spring. 
Eventually, Parker and Malone learned not only that the vaccine re- 
mained potent after a year's storage but also that a more potent vaccine 
resulted if ticks were stored in the cold room for a year before being 
used. Preservatives posed another problem. CarboUc acid, or phenol, 
was originally used, but it was found insufficient to kill all contami- 
nating organisms. Parker switched to formalin for a period, but it 




Tubes containing ticks were stoppered with cotton to permit oxygen to en- 
ter. Their open bottoms were buried in the damp earth. (Courtesy of the 
Rocky Mountain Laboratories, NIAID.) 




A laboratory technician decants Spencer-Parker vaccine into bottles for 
shipment, 193 1. (Courtesy of the Rocky Mountain Laboratories, NIAID.) 



The Spencer-Parker Vaccine 



135 



caused the vaccine to appear cloudy. Finally he adopted a combination 
of the two preservatives. Although the formalin caused a slight stinging 
for about five minutes after a patient was injected, it ensured a sterile 
product and generated no other side effects. 

The standard method finally adopted was expensive, time-consum- 
ing, and dangerous. It required four to six thousand rabbits and twenty 
to thirt)' thousand guinea pigs for feeding the ticks in all stages of their 
development, for maintaining passage strains of spotted fever, and for 
potency testing of the vaccine. Initially, field workers collected thirty 
to iorvy thousand adult ticks, which were placed on rabbits to feed 
and mate. After mating, the male ticks died. The females were collected 
and placed on a wire cloth over moist sand on a tray in an incubator, 
where they produced some hundred million eggs and then died them- 
selves. 

Approximately 80 percent of the eggs hatched into larvae after a 
five- to six-week incubation period. At this point, adult female rabbits 
were infected with spotted fever. On the first day the rabbits ran a 
high fever, they were placed in "infesting bags," to which the larvae 
of four female ticks were added. This number was the maximum that 
could feed without exsanguinating the rabbits. Left alone for twenty- 
four hours, the larvae attached to the rabbits and the bags could be 
removed. Rabbits and ticks were placed in wire cages and covered 
with white cage bags to prevent the ticks from escaping. After four or 
five days, about one-fourth of the larvae succeeded in engorging and 
dropped from the rabbits to be caught in the cage bags. 

The next step involved empt\'ing the cage bags into a "tick picker" 
containing a series of screens designed to separate out waste food and 
rabbit feces from the larval ticks. The recovered larvae were put back 
into the incubator to molt into nymphs, a process that took about a 
month. The feeding process was then repeated on a new series of 
infected female rabbits, although fewer nymphs — about four hun- 
dred—were placed on each rabbit. After the engorged nymphs were 
separated by the tick picker, they were washed and separated from 
further debris in a converted cream separator and dried with a hair 
drier. Next they were placed in pillboxes, nvo hundred nymphs to a 
box, and returned to a low^ humidit)- incubator at zz° C for several 
weeks until they molted into adults. About one million of the one 
hundred million original eggs survived to adulthood. They were stored 
for six months to a year in a refrigeration room that simulated a normal 
Montana mountain winter temperature. 

When ready to be used for vaccine production, the ticks were taken 
from storage and placed into a "tick separator," an ingenious device 



1^6 



Rocky Mountain Spotted Fever 



in which hve ticks were separated from dead ticks and any cast skin 
from the last moh. The separator consisted of a cyHndrical sheet metal 
container, into which the stored ticks were placed, and an attached 
glass tube. In a lighted cabinet, the ticks migrated toward the Hght— 
that is, into the glass tube— leaving the dead ticks and refuse behind. 
These ticks were warmed in the incubator and fed on guinea pigs for 
three days to reactivate the virus. They were then soaked for twenty- 
four hours in a Merthiolate solution to sterilize the surface of their 
bodies, after which they were divided into lots by weight. Covered 
with a salt solution containing a 2 percent mixture of phenol and 
formalin, each lot was emulsified in a Waring blender for two minutes. 
To the deep orange liquid produced was added additional phenol- 
formalin-saline diluent to bring the volume to 200 cc. This crude 
vaccine was stored for a week at room temperature to kill the rickettsiae 
and any contaminating organisms. 

Finally, the vaccine was diluted with another 600 cc of saline without 
additional preservatives, bringing the volume to nearly a quart and 
reducing the concentration of the phenol-formahn preservatives to 0.5 
percent. The vaccine thus produced contained one "tick equivalent" 
in each cc. After a few additional weeks of storage in a cold room, 
the vaccine was centrifuged in order to remove the tick tissue. Guinea 
pigs were inoculated with each lot of vaccine to test potency, and 
sterility tests were performed by the biologies control section of the 
Hygienic Laboratory in Washington, D.C. The lots that passed these 
tests were bottled, labeled, and shipped."^^ 

The enthusiastic reception given the tick vaccine across the north- 
western states was welcome, but some of the attendant publicity was 
not so well received. Bitterroot Valley residents, acutely sensitive to 
spotted fever's effect on property values, were outraged in 1927 when 
Paul de Kruif chronicled the saga of vaccine development for the 
magazine Country Gentleman. A former bacteriologist who had 
abandoned his career at the Rockefeller Institute to become a popular 
science writer, de Kruif was renowned for his hyperbolic style. Al- 
though a generation of scientists was inspired by de Kruif's book 
Microbe Hunters^ residents of the Bitterroot found little to praise in 
his description of their valley crouching in fear of spotted fever. "When 
the snow begins to rnelt on the hills the terror of the spotted fever 
begins to stalk in the Bitter Root Valley," de Kruif wrote. "In that sad 
territory the doors of the empty ranch houses creaked and whined on 
the hinges, singing a lonesome song for fathers who had died and 
brothers and sisters and mothers who had gone away." De Kruif's 
style riveted readers and sold magazines, but Bitterroot businessmen 



The Spencer-Parker Vaccine 



137 



were convinced that the article would discourage prospective home- 
owners and businesses from purchasing land in the valley."^^ 

Shortly after the article was published, the Northwest Tribune ran 
an article under the banner headline "Bitter Root Valley Is Up in Arms." 
Missoula and other Montana cities were also reported to be "ablaze 
with a wave of indignation." Commercial clubs in Victor, Stevensville, 
and Darby joined with the Hamilton Chamber of Commerce to send 
a prote^ing telegram to the editors of Country Gentleman. Another 
article called de Kruif 's story an "absurd fairy tale." Believing that de 
Kruif must have obtained material for his story from employees of the 
schoolhouse laboratory, George L. Knight, secretary of the Hamilton 
Chamber of Commerce, wrote Montana Congressman Scott Leavitt, 
requesting that laboratory employees be restricted in what they could 
say to reporters. "We have no objection whatever to the facts being 
printed," Knight asserted. "The statements that we do object to are 
the ones which have in the past been dressed up by information ex- 
aggerated and over-drawn." Surgeon General Gumming responded, 
but his instructions were couched as "merely a caution" that employees 
should be careful what they said to the press, so information would 
not be abused.^^ 

It was not only articles in the popular press that elicited hostility 
from the guardians of the valley's public image. In 1926, W. F. Cogs- 
well, secretary of the Montana State Board of Health, found himself 
at the center of unintended controversy. A man from Dillon, Montana, 
whose daughter's geology class at Vassar College was scheduled to 
make a field trip to the west side of the Bitterroot, inquired of Cogswell 
whether the outing would be safe. Cogswell replied that, as state health 
officer, he would do all in his power to prevent such a field trip in the 
spring. This letter stimulated an "indignation" meeting of the Hamilton 
Chamber of Commerce, whose secretary threatened "dire and sundry 
things" against Cogswell, including trying to get him fired. In the view 
of the Chamber of Commerce, Cogswell had gone out of his way "to 
give the Bitter Root Valley a black eye." When pressed, however, 
secretary Otto Bolen admitted that he would not want his own daughter 
going into the Bitterroot mountains during active tick season, and he 
agreed to discuss with Cogswell how future inquiries should be han- 
dled.^^ 

Although the danger of living in the Bitterroot Valley was period- 
ically overstated or minimized, the peril in which the staff of the 
schoolhouse laboratory worked was never questioned. In August 1926, 
Ralph R. Parker suffered an especially bad moment. His wife Adah 
found a tick attached to herself that, when tested, produced spotted 



138 



Rocky Mountain Spotted Fever 



fever in laboratory guinea pigs. Fortunately, Mrs. Parker had been 
vaccinated in May, and the tick was discovered before it had become 
well engorged. She showed preliminary symptoms of spotted fever but 
never came down with a full case. A relieved Parker noted: "The facts 
appear to be good circumstantial evidence of the value of the vaccine, 
but it is far from a pleasant thing to accumulate evidence from one's 
own wife. The curse of this work is not the danger to one's self but 
the continual fear of bringing infection home."^° 

With the discovery of tularemia in the laboratory's rabbits, more- 
over, another hazard was added to the burden under which researchers 
and their staff labored. In May 1925, Earl W. Malone, the chief vaccine 
maker, contracted tularemia. His incapacitation brought to six the 
number of spotted fever or tularemia infections among the laboratory 
staff in just one year. Infected ticks from the vaccine-making process 
often were found attached to laboratory personnel, and the school- 
house design of the laboratory even allowed dogs to wander in oc- 
casionally. As the dangers compounded, the staff came to believe that 
the only way to make the work safer was to build a new laboratory.^ ^ 

Beginning in early 1925, the Montana State Board of Entomology 
explored possible sources of funding for a new facility, the total cost 
of which was estimated to be fifty thousand dollars. Robert A. Cooley 
wrote to the Anaconda Copper Mining Company, the Rockefeller 
Foundation, and the U.S. Public Health Service, but all hesitated to 
commit the necessary monies. Since spotted fever was known only in 
the northwestern states, the Service preferred that these states pool 
their funds to support vaccine production. Although some interest was 
expressed by a former state health officer in Wyoming, none of the 
northwestern state governments appropriated funds for the venture. 

In early 1926 the quest for a new laboratory took on additional 
urgency when the original owners of the schoolhouse laboratory pe- 
titioned to recover their property. A stipulation in the deed provided 
that the property would revert to the Waddell family if the building 
ceased to be used as a school. Since the Waddells had "mentioned a 
price at which they would sell," Cooley presumed that their aim was 
"to get a sum of money from somebody for the property."^^ The school 
board opposed the petition, claiming that a population increase might 
eventually require that the building be reclaimed as a school. In 1927 
a court hearing the case decided in favor of the Waddells. 

The Montana State Board of Entomology seized upon this ruling to 
press the state legislature for a new building. Old friends of the spotted 
fever researchers came to their aid in this effort. S. Burt Wolbach, who 
stopped at the laboratory during a western trip, felt compelled to write 



The Spencer-Parker Vaccine 



139 



Hygienic Laboratory director George W. McCoy that he considered 
the schoolhouse "the most dangerous place" he visited. Describing 
laboratory conditions as disgraceful, Wolbach asked McCoy's help in 
moving federal or state authorities to secure a new facility. W. F. 
Cogsv^ell, secretary of the state board of health, also appealed to the 
surgeon general for documentation that w^ould impress the state leg- 
islature. Surgeon General Gumming complied, intimating that a new 
laboratory w^as necessary to "make continued studies by Service per- 
sonnel possible. "^'^ 

When the state legislature convened in January 1927, it appropriated 
sixty thousand dollars to build a nev^ laboratory and twenty-five thou- 
sand dollars per year for operating expenses during the next biennium. 
Once the question of funding had been resolved, another prickly issue 
arose: where should the new laboratory be located? Spencer argued 
for Missoula, a larger town than Hamilton and home of the University 
of Montana. Faculty members favored such a move, and Spencer as- 
serted that the infected ticks posed no threat to the campus. "I carry 
yearly thousands of infected ticks with me to Washington, and ship 
hundreds more to New York and abroad." The state board of en- 
tomology, however, preferred that the new laboratory be located in 
Hamilton. Because of additional research planned by the board, Gooley 
stated, "we need to be nearer to the field than we would be in Missoula. 
For the vaccine work I think we could have gotten along very nicely 
as far away as Missoula but, all things considered, the Board was of 
the opinion it would be better at Hamilton." The board's position 
prevailed when the Hamilton Chamber of Commerce purchased and 
donated to the state a tract of land on which the laboratory would be 
built.^^' 

Many Bitterroot Valley residents vehemently opposed the location 
just outside the business district in Hamilton, in an area known as 
Pine Grove. Of primary importance was that, for the first time ever, 
a spotted fever laboratory was to be built on the uninfected east side 
of the river. Since no one knew why spotted fever was restricted to 
the west side, it is not surprising that there was opposition to a facility 
that would be rearing miUions of infected ticks in a previously safe 
area. For two decades, furthermore, the economic fortunes of the 
Bitterroot Valley had fluctuated with the success or failure of schemes 
to irrigate the dry benchlands. In 1920, after the collapse of one of 
these efforts, a bankruptcy court had ordered residents to form an 
irrigation district to raise needed water revenues. The president and 
Board of Commissioners of this new Bitter Root Irrigation District 
viewed a laboratory in Hamilton as a threat. Siting it there, they 



140 



Rocky Mountain Spotted Fever 



protested, would "cause a general feeling that the entire valley was so 
infected, causing unjust damage to the East Side farming lands."^^ To 
protect their interests, they filed suit against the state boards of health 
and entomology and against the state board of examiners. 

Most of those complaining were residents of Pine Grove who felt 
that their own property values were threatened. E. R. Hammond, an 
employee of the local Light and Water Company, described as the 
"principal agitator," was joined by other prominent Hamilton resi- 
dents, including a physician, a dentist, a pharmacist, a judge, and an 
engineer for the Bitter Root Irrigation Company. When the first stir- 
rings of opposition appeared, proponents of the new laboratory dis- 
missed it as "Cigar Store, Drug Store, Bridge Club and street corner 
discussion." Although the case remained on the court's calendar, a 
number of the plaintiffs soon dropped out, realizing that they would 
be responsible for court costs if the ruling went against them.^^ 

Cooley welcomed this fight. He believed that erecting the laboratory 
in Hamilton would do much to clear away superstition that had sur- 
rounded spotted fever for decades. He thus rebuffed an alternative 
proposal from Victor officials, who hoped to entice the laboratory to 
their city. Setting out his opinions in a letter to Cogswell, Cooley stated: 

The psychological influence of bringing this laboratory into town will be 
considerable. One great difficulty in the past has been that people have looked 
upon spotted fever as a mystery about which the less said the better. There 
has been too much unreasonable fear of it. To bring the laboratory into town 
will help, gradually, to allay unreasonable fear, and will help to educate 
everyone. Some day residents in that vicinity will say to visitors who come to 
the valley that "We used to be afraid to go across the river. Now we have the 
laboratory right in town." This will do much to reassure people who think 
of settling and making business investments.^^ 

On 27 July 1927 the case was heard by Judge George B. Winston 
of the Fourth Montana Judicial District. The plaintiffs' testimony fo- 
cused on the dangers already documented at the schoolhouse labo- 
ratory. Field assistants were described as coming back with ticks "on 
their horses and clothing, and their beds, and they will ride up to the 
institution." Since field workers were seeking "the most malignant and 
wild — the most virulent and dangerous ticks," there was fear that they 
would carry them home if the laboratory was in Hamilton. It was 
noted that ticks had escaped in the yard of the laboratory and alleged 
that the janitor had been "the sole protector of the community." Coun- 
tering suggestions that children playing near the proposed site would 
be at risk, Cogswell testified that there would be no chance for the 
experimentally infected ticks to escape from the laboratory. The vivid 



The Spencer-Parker Vaccine 



141 




Built by the state of Montana in 1928 for spotted fever vaccine production, 
this laboratory was located in Hamilton, Montana, on the uninfected east 
side of the Bitterroot River. To prevent infected ticks from escaping, it 
incorporated many special features, such as rounded seams where walls met 
floors and a moat around its perimeter, across which ticks reportedly could 
not swim. (Courtesy of the Rocky Mountain Laboratories, NIAID.) 

testimony caught the attention of the Journal of the American Medical 
Association, which reported that "the question of how fast these ticks 
travel is said to have enlivened the court proceedings." Judge Winston 
ultimately sided with the researchers and ruled that construction of 
the laboratory, begun in mid June, should continue. 

With the court case behind them, the sponsors of the new laboratory 
concentrated on tick proofing the facility, which was occupied in May 
1928. The laboratory was built of reinforced concrete, brick faced. 
Around the perimeter of the building was a moat containing water, 
across which ticks supposedly could not swim. Outside it was a "tick 
yard," used, in part, for storing hibernating ticks. An animal house 
was attached to the main building, and the whole complex was sur- 
rounded by a fence to keep out "rodents, domestic animals, and boys." 
In addition to several laboratory rooms, refrigeration rooms, and gen- 
eral offices, there were specially designed tick-rearing and vaccine- 
producing rooms. The joints between floor and walls were all rounded 
to prevent ticks from hiding. A chamber through which workers passed 
on entering or leaving the tick-rearing room contained mirrors for 



142. 



Rocky Mountain Spotted Fever 



examining their bodies. Eventually a device v^as also installed to heat 
their stored clothing to 150° F for six minutes in order to kill any ticks 
hiding in the fabric seams. 

These extraordinary precautions, soHcitous public relations, and 
evidence that no children playing near the laboratory became infected 
soothed the tensions raised by construction of the facility. Within a 
few years, in fact, the problem reversed itself: townspeople visited the 
laboratory so often as to make themselves a nuisance. It had become, 
Cooley noted, "a rather popular place for visitors to go. People in 
town like to take their guests out there and show them through the 
building." Fearing that an accidental infection might take place, Parker 
ordered all employees to get permission before taking visitors through 
the building.^^ 

Parker had some cause for concern, because even with the best advice 
on constructing the building, unanticipated dangers were eventually 
discovered. Infected ticks were found hiding around the windows and 
screens, in a pile of sacks that had lain undisturbed for some time in 
the corner of a room, and in the nickel caps around pipes going through 
the floor. Ticks also escaped via the cage sacks used in the tick-rearing 
process. After each use, these sacks were sent down a chute into a 
creosote solution that was supposed to kill any remaining ticks before 
the sacks were washed. The solution was discovered to be ineffective 
when ticks were found in the laboratory's backyard where the sacks 
were dried. Subsequently the bags were soaked in kerosene and boiled 
in soap before washing.^^ 

Ironically, none of these precautions would have prevented a lab- 
oratory-acquired spotted fever infection that occurred at the school- 
house laboratory just three months before the new facility was com- 
pleted. No infected tick was found attached to LeRoy Kerlee, a 
Bitterroot Valley native and student volunteer at the laboratory, who 
became ill on 4 February 1928. W. F. Cogswell speculated that Kerlee 
might have contracted the disease through a skin abrasion or by rub- 
bing his eye with a contaminated finger. Because Kerlee had received 
injections of the Spencer-Parker vaccine, his illness provoked suspicions 
among some local doctors that the vaccine itself had caused the disease. 
Roscoe R. Spencer and Ralph R. Parker launched an immediate in- 
vestigation of the case, which revealed that the young man had not 
received the full vaccine regimen. On i and 6 September 1927, Kerlee 
had received i and 2 cc, respectively, of vaccine— whereas two injec- 
tions of 2 cc each were the norm. Spencer's research had shown that 
the vaccine's protective power lasted only a few months, so Kerlee's 
immunity had probably not been carried over into 1928. On 30 January 



The Spencer-Parker Vaccine 



143 



1928, Kerlee had taken i cc of vaccine, only one-fourth of the complete 
series. Records on the lot of vaccine shovv^ed that it had protected all 
six guinea pigs on which it was tested. Parker speculated that Kerlee 
had been infected either before receiving the 1928 injection or almost 
immediately thereafter. 

There was some indication that these minimal doses of vaccine 
affected the course of Kerlee's illness. Four days after the onset of 
symptoms, he seemed to rebound. He got out of bed and shaved but 
soon felt exhausted. This short period of remission, Parker beheved, 
indicated that the virus and the antibodies produced by the vaccine 
were "fighting" and that the vaccine almost won on that morning. 
When Kerlee's temperature shot up to 104° F that same afternoon, he 
was taken to the hospital. His condition deteriorated rapidly, and a 
week later, on 15 February, he died. In death the promising young 
scientist was honored almost like a military hero. His brother, refusing 
to be intimidated by the deadly disease, applied before the funeral for 
a position at the laboratory. 

Kerlee's death unsettled Bitterroot citizens and threatened the vac- 
cine program at the laboratory. In an effort to allay fears, Cogswell 
published a newspaper article trying to explain to Bitterroot Valley 
residents that this singular case did not invalidate the effectiveness of 
the Spencer-Parker vaccine. He noted that occasionally vaccines failed 
in individuals even though they were effective on a broad scale. Fur- 
thermore, he argued, the spotted fever strains maintained at the lab- 
oratory were the "most virulent form of the poison, much more virulent 
than that found in nature." At the laboratory itself, a morose Spencer 
wrote Surgeon General Gumming that the situation had "caused a 
gloom to be cast over our personnel." Not only had they lost a friend, 
Spencer noted, but fear generated by the death had prompted Lawrence 
McNeal, who was in charge of the infected-tick-rearing room, to resign 
effective 20 February. "This position in the tick room is the most 
dangerous in our laboratory," Spencer observed, and informed the 
surgeon general that it was impossible to replace McNeal with another 
immune individuals^' 

Spencer's depression hastened his decision to leave Montana. In 
contrast to his U.S. Public Health Service colleague Lunsford D. Fricks, 
Spencer had never come to love hving in the Bitterroot Valley. Both 
he and his wife preferred the sophistication of Washington, D.G., to 
the isolation of Hamilton, and neither enjoyed the Bitterroot's cool 
climate. Uneasy with the dangers of spotted fever research, Mrs. Spen- 
cer was "very anxious" that her husband finish his work and move 
on into something new. Spencer himself admitted that the intellectual 



144 



Rocky Mountain Spotted Fever 



challenge of the work lay in vaccine development— the mechanics of 
vaccine production did not interest him. He therefore asked for and 
was granted orders relieving him of duty in Montana at the end of 
the summer of 1928.^^ 

Over the next two years, as credit for their achievement began to 
be accorded to Spencer and Parker, the old physician-entomologist 
rivalry surfaced momentarily. In August 1928, Parker presented a paper 
on the spotted fever work to the Section on Medical and Veterinary 
Entomology of the Fourth International Entomological Congress at 
Ithaca, New York. Spencer learned from a friend that Parker never 
mentioned Spencer's name.^^ This news arrived while Spencer was 
preparing an exhibit for the American Medical Association. Reacting 
in an admittedly vindictive manner, he left Parker's name off the ex- 
hibit, which was awarded the 1930 Billings Medal by the association.^^ 
Except for this unfortunate display by both men, the two regarded 
each other highly. After Spencer left Montana, he held a variety of 
positions within the U.S. Public Health Service. From 1943 to 1947 
he served as the second director of the National Cancer Institute. After 
retiring from the Service in 1952, Spencer lived thirty more years in 
retirement. He died 10 January 1982 in Virginia. He published several 
popular articles on spotted fever, hoping to educate the public about 
the disease and about the methods of medical research. 

With Spencer's departure from Montana in 1928, Parker was des- 
ignated a special expert by the Service and placed in charge of the new 
laboratory, despite some concern that his lack of an M.D. degree would 
strain the laboratory's relations with physicians. Fricks, who made 
yearly inspection tours in the northwest states for the Service, thought 
the state health officers would find it "more agreeable" if "a medical 
officer were again placed in charge of these activities," but Service 
administrators supported Parker's appointment. The surgeon general 
commented that "Dr. Parker's excellent work should break down any 
opposition to him on the part of doctors in the Northwest." Indeed, 
although Parker did not acquire another professional staff member 
until October 1930, he managed to supervise vaccine production while 
continuing his studies on the natural history of spotted fever. Parker's 
appetite for work, his maintenance of detailed records, and his careful 
attention to correspondence won him the respect and admiration of 
Service officers and state health officials alike. 

A thornier problem concerned long-term funding for vaccine pro- 
duction. The Montana state legislature constructed the laboratory 
building, and the State Board of Entomology conducted field inves- 
tigations on entomological problems, but neither wanted to support 



The Spencer-Parker Vaccine 



145 




In 193 1 people lined up outside this school in Darby, Montana, to be 
vaccinated against spotted fever at a free clinic sponsored by the U.S. Public 
Health Service. R. R. Hayward, M.D., a local physician, administered the 
vaccine. (Courtesy of the Rocky Mountain Laboratories, MAID.) 



the costly vaccine program. The U.S. Public Health Service had agreed 
to fund vaccine development, assuming that a successful product v^ould 
be produced commercially or by state health departments. Producing 
a vaccine from ground-up ticks, however, limited the location of any 
production facility and imposed costs and dangers that made it an 
intimidating venture. George W. McCoy, director of the Hygienic 
Laboratory, summed up the dilemma when he toured the northwest 
states in April 1928 to assess the impact of the Spencer-Parker vaccine. 

The question as to the means of supplying the vaccine ultimately, if the early 
promising results of its use are fulfilled, is a difficult one. No commercial firm 
is likely to be interested in its manufacture and sale. It seems to be an un- 
profitable field for the Service once the research features are disposed of and 
for each state to manufacture its own supply would be most wasteful by reason 
of the necessity for the duplication of plant and personnel. Perhaps a pooling 
of the interests of the several states concerned would be the logical procedure."^ 

Although the future of vaccine production remained uncertain, most 
people in the Bitterroot Valley and in other western areas welcomed 



Rocky Mountain Spotted Fever 



the vaccine, accepting its theoretical underpinnings about microor- 
ganisms, antibodies, and tick transmission without the skepticism that 
had characterized their forebears. Parker's statistics and their own 
experience vaHdated the vaccine's effectiveness. Scientifically the Spen- 
cer-Parker vaccine was a tour de force, the first human vaccine prepared 
from the bodies of arthropod vectors and the first effective medical 
intervention against spotted fever. Spencer and Parker owed much to 
the earlier investigators who had struggled with Rocky Mountain 
spotted fever for more than two decades as well as to international 
research on typhus and its related maladies. Their own ingenuity and 
persistence, however, especially in culturing rickettsiae in their tick 
hosts and in devising the complex process for making the vaccine, had 
produced the long-sought preventive, and for that achievement they 
won the respect and gratitude of people throughout the Rocky Moun- 
tain states. 



Chapter Eight 



Spotted Fever 
outside the Rockies 

Disease is very old and nothing about it has changed. It is we who change 
as we learn to recognize what was formerly imperceptible. 

John Martin Charcot, De I'expectation en medecine 



In 1926, a young girl in Terre Haute, Indiana, was playing in a pile 
of gravel when she discovered a "brown and black bug the size of a 
'butter bean' " attached to her scalp behind her right ear. Although 
she had not been out of the immediate vicinity, she later developed a 
high fever and headache, which were accompanied by a rash and a 
"pronounced sleepy condition" from which it was difficult to rouse 
her even for food, Uquids, and medication. Her physician diagnosed 
Rocky Mountain spotted fever. ^ Similar isolated cases of spotted fever 
outside the Rocky Mountain region had been reported, but their num- 
bers seemed too small to be significant. 

East of the Mississippi River, physicians usually diagnosed cases 
displaying the symptom complex of high fever, headache, stupor, and 
a rash as typhus fever or Brill's disease. These two diseases had been 
viewed as identical since 19 12, when John F. Anderson and Joseph 
Goldberger demonstrated that Brill's disease and epidemic typhus fever 
produced cross-immunity in guinea pigs. Brill's disease, with its milder 
clinical course and lower mortality, often became the default diagnosis 
when physicians encountered typhus-like symptoms with no reports 
of Hce or of contagiousness.^ In 1926, however, U.S. Public Health 
Service investigator Kenneth F. Maxcy demonstrated in a brilliant 
epidemiological study that an "endemic" form of typhus existed in 
the southeastern states. Although clinically indistinguishable from ep- 
idemic typhus, endemic typhus produced a lower mortality rate, con- 
sistently under 5 percent. Classic, epidemic typhus was clearly con- 
tagious, while endemic typhus occurred sporadically. No lice were 
associated with endemic typhus cases, but some sort of vector seemed 
to play a role in the disease. Maxcy suggested that a parasite of the 



147 



148 Rocky Mountain spotted Fever 

rat might be one potential vector. Since no arthropod vector had been 
associated w^ith Brill's disease, it appeared that endemic typhus rep- 
resented a third distinct manifestation of typhus.^ 

Maxcy's work did not explain the odd cases of typhus-like symptoms 
in the east that varied from all three patterns. In 1930, for instance, 
a Virginia physician, R. D. Glasser, reported a case of typhus-like fever 
following the bite of an Amblyomma americanum tick. This tick, 
though known as an occasional parasite of man, had never before 
been implicated in the transmission of disease. Glasser also thought 
the case noteworthy because animals injected with the victim's blood 
did not show typical typhus signs. Moreover, the Weil-Felix test for 
typhus produced consistently negative results."^ 

Glasser's report might have remained yet another medical curiosity 
had not the National Capital Area itself suffered an increase in what 
were presumed to be endemic typhus cases in 1930. In late June the 
Washington Post noted several cases from Alexandria and Fort Hum- 
phreys, Virginia, northward through rural Maryland. Additional cases 
were soon reported, one in the city of Baltimore. By mid July, when 
nineteen cases with five deaths had been reported, federal and state 
health officials from Virginia, Maryland, Delaware, and Pennsylvania 
held a conference in Baltimore and agreed to cooperate in a broad 
epidemiological and laboratory study of the typhus problem.^ 

Representing the federal government at this meeting was U.S. Public 
Fiealth Service officer RoUa Eugene Dyer, who had taken up Kenneth 
F. Maxcy's work on typhus in 1929, when Maxcy resigned from the 
Service to accept an appointment at the University of Virginia. Born 
in Ohio and reared in Kentucky, Dyer had studied medicine at the 
University of Texas Medical Branch.^ He entered the Service in 19 16 
and rose rapidly through the ranks, rotating through the usual duty 
stations until 1921, when he joined the Hygienic Laboratory staff. 
Within a year, he had been named assistant director of the laboratory. 
In 1925 he published an authoritative paper on scarlet fever antitoxin, 
and in 1929 the laboratory director, George W. McCoy, asked him to 
set up a typhus unit, assigning two Service officers, Lucius F. Badger 
and Adolph S. Rumreich, to assist him. 

Dyer, Badger, and Rumreich operated out of laboratory buildings 
at Twenty-fifth and E Streets, N.W, in Washington, D.C. These red 
brick buildings had housed the Hygienic Laboratory since 1904, and, 
after the laboratory was renamed the National Institute of Health 
(NIH) in May 1930, they remained the principal locus of service 
research until 1938, when operations were transferred to a much larger 
campus in Bethesda, Maryland.^ In their laboratory the NIH typhus 



spotted Fever outside the Rockies 



149 



Rolla E. Dyer, who headed 
the National Institute of 
Heahh (NIH) typhus unit 
and later served as director 
of the NIH, demonstrated in 
193 1 that Rocky Mountain 
spotted fever was also pres- 
ent on the east coast of the 
United States. (Courtesy of 
the National Library of 
Medicine.) 

team injected blood from a Virginia case into guinea pigs, hoping to 
establish a strain of typhus in the experimental animal. Before con- 
clusive observations could be made, Dyer was called to Garfield Hos- 
pital in Washington to see a case diagnosed as typhus fever. He asked 
Roscoe R. Spencer to go v^ith him and provide an additional opinion. 
"We sav^ the patient and decided that the doctor w^as right, that the 
patient had typhus fever," Dyer recalled in an oral history memoir, 
"but as we w^alked down the hill, Spencer remarked, 'If I had seen 
that case in Montana, I would have called it spotted fever.' " Spencer's 
uncertainty triggered a new line of thinking in Dyer's mind. Upon 
returning to the NIH, he sent to Montana for a strain of spotted fever, 
which he established in guinea pigs. When he tested it against those 
strains isolated from rural Virginia patients, he had a clear answer: 
the rural cases were not typhus at all. They were Rocky Mountain 
spotted fever. ^ 

Armed with this critical information. Dyer, Badger, and Rumreich 
launched a full-scale study of the two diseases along the eastern sea- 
board. "Most of the cases living in rural districts," they reported, as 
well as "urban dwellers vacationing in the country, suffered from a 
very severe disease, which did not correspond to the clinical picture 
of endemic typhus, and which resembled spotted fever of the Rocky 
Mountains more closely than it did any other disease. A quite high 
proportion of these cases gave a history of tick bite within a short 
time preceding onset." They analyzed the geographic distribution, gen- 




I50 



Rocky Mountain Spotted Fever 



eral symptoms, nervous and mental symptoms, and complications of 
ICQ selected cases that included both Rocky Mountain spotted fever 
and typhus. Disturbances of the central nervous system were more 
severe in the patients with spotted fever. Convalescence was more 
prolonged and was often accompanied by deafness, visual disturbances, 
slurred speech, and mental confusion that persisted for weeks. No 
deaths occurred among the endemic typhus cases, while among "93 
cases of the Rocky Mountain spotted fever type ... 21 died— a case 
fatality rate of zz.6 percent." The Journal of the American Medical 
Association found this work of great interest. It would "help to clear 
up another obscure type of disease," the Journal opined, "and will 
place the public in the eastern part of the United States on guard 
against being bitten by ticks. "^ 

One key question, however, remained unanswered. How did the 
victims of typhus and Rocky Mountain spotted fever contract their 
illnesses? Almost half of the spotted fever cases reported a definite 
history of tick bite within three weeks before the onset of symptoms. 
A few victims remembered crushing engorged ticks removed from dogs. 
All the cases, moreover, occurred under conditions in which tick bite 
was possible. In contrast, the relation between victims of endemic 
typhus and any arthropod was less clear. The epidemiological evidence 
confirmed Maxcy's suggestion that rodents were somehow involved: 
78 percent of the typhus cases had occurred in close association with 
rats. Only 16 percent of typhus victims, however, reported actual 
contact with rats and only 8 percent recalled having received flea bites. 
To answer these questions, the NIH typhus unit launched another 
study. Experimentally, they soon demonstrated that spotted fever could 
be preserved in the body of the American dog tick, Dermacentor 
variabilis. The key to demonstrating tick transmission, however, was 
locating infected ticks in nature. By 1932, Badger accompHshed this, 
collecting naturally infected D. variabilis from a farm in Virginia on 
which a human case had occurred. ^° 

Even before the spotted fever vector was confirmed, the typhus unit 
recovered typhus rickettsiae from fleas on rats caught at typhus foci 
in Baltimore, Maryland, and in Savannah, Georgia. Dyer announced 
this exciting finding in a paper presented at the 193 1 annual meeting 
of the American Medical Association. The news precipitated animated 
discussion among other rickettsial researchers present. Hans Zinsser 
of Harvard University Medical School, who, with his Mexican col- 
laborator M. Ruiz Castaneda and a Swiss pathologist, Herman 
Mooser, had recently demonstrated that rats were one reservoir of 
endemic typhus fever in Mexico, was not convinced that fleas were 



spotted Fever outside the Rockies 




The common dog tick, Dermacentor variabilis, is the principal vector of 
spotted fever in the eastern United States. (Courtesy of the Rocky 
Mountain Laboratories, NIAID.) 

the sole vector. Zinsser favored the bedbug because of his personal 
experience in Vera Cruz, Mexico, a town teeming with rats and fleas 
but free from typhus. Kenneth F. Maxcy argued that epidemiologic 
evidence clearly ruled out bedbugs, and Rolla E. Dyer buttressed Max- 
cy's position by noting that Zinsser himself admitted the possibiUty 
of mild or subclinical cases of unrecognized typhus in Vera Cruz.^^ 

This debate reflected the vigor of rickettsial research in the early 
1930s. Zinsser optimistically predicted that both typhus and spotted 
fever investigations in the United States were reaching a "coordinating 
phase" because of "a gradual encirclement" by epidemiologic and 
experimental methods. His positivism was doubtless influenced by 
the expansion of knowledge about typhus in Mexico to which Zinsser 
and his associates had recently contributed. Their discoveries had 
helped to estabUsh additional criteria by which typhus-hke diseases 
across the globe, including Rocky Mountain spotted fever, could be 
studied. 

The disease called tabardillo, or Mexican typhus fever, for example, 
changed scientific identities during the studies of Zinsser, Castaneda, 
and Mooser. The Mexican people had used the descriptive term, mean- 
ing "red cloak" to describe fevers that exhibited a particular symp- 
tomatic rash, whether they occurred in summer or winter and whether 



152 



Rocky Mountain Spotted Fever 



the mortality was high or low. When Howard Taylor Ricketts, Joseph 
Goldberger, and John F. Anderson studied "tabardillo" in Mexico City, 
they saw an epidemic, louse-borne disease that occurred during the 
winter and spring months. By the late 1920s, however, researchers 
began to realize that the endemic typhus fever described by Maxcy 
was also widespread in the Mexican highlands. Also called tabardillo, 
this disease occurred primarily in the summer and fall and exhibited 
a low mortality. During the intensive investigation of this new disease 
that followed, the name tabardillo, as well as the phrase Mexican 
typhus fever, soon became identified solely with endemic typhus. Ep- 
idemic typhus in Mexico became known as European typhus in order 
to distinguish it.^^ 

In 19 17, before this distinction had been made, U.S. Public Health 
Service officer Mather H. Neill had described a scrotal reaction in 
guinea pigs infected with "typhus fever" from the Mexican highlands. 
Although Neill noted that it was milder than the reaction induced by 
spotted fever, it had not been observed in guinea pigs inoculated with 
European strains of typhus or with Brill's disease. Neill's paper was 
nearly forgotten until 1928, when Mooser cited it to support his own 
similar findings. He also described cells packed with rickettsiae in the 
tunica vaginalis, the lining over the testes. These cells came to be called 
Mooser cells, and the tunic reaction in guinea pigs, which served as a 
test to distinguish between endemic and epidemic typhus, became 
known as the Neill-Mooser phenomenon.^'* This form of typhus fever 
was generally transmitted by the rat flea, but if introduced into a louse- 
infested population, it could become epidemic like its better-known 
relative. Mooser thus pointed out that the name endemic typhus was 
not truly descriptive. In 1932 he proposed the name murine typhus 
to indicate that the disease was a natural infection of the rat.^^ 

Although such new information helped to distinguish epidemic and 
murine typhus, Brill's disease remained a puzzling phenomenon. In 
the laboratory it appeared to be identical with epidemic typhus, yet 
its milder symptoms resembled the murine disease. In 1934, Zinsser 
conducted an epidemiological study as rigorous as Maxcy's work on 
murine typhus that identified victims of Brill's disease as European 
immigrants who had come from regions where epidemic typhus was 
prevalent. He concluded that Brill's disease— later called Brill-Zinsser 
disease— was really a recrudescence of an earlier attack of epidemic 
typhus. This indicated, Zinsser argued, that typhus rickettsiae could 
remain dormant in the human body, making typhus a disease in which 
humans, rather than rodents or arthropods, served as the natural 
reservoir. If a patient with Brill's disease was fed on by Hce, the insects 



spotted Fever outside the Rockies 



153 



could become infected and transmit the disease to others. By this means, 
apparently spontaneous epidemics of typhus might be started. Labo- 
ratory studies in the early 1950s confirmed Zinsser's epidemiological 
reasoning. 

Across the Atlantic Ocean, Sir William Hames declared at a 1930 
meeting of the Royal Society of Medicine in London that "typhus in 
the tropics" was "coming to judgment like a Daniel," with research 
"throwing much new light upon dark corners of the epidemiological 
world." The paper that eUcited Hames's enthusiastic comment was 
given by William Fletcher, a British physician working in Kuala Lum- 
pur, capital of the Federated Malay States. In a review of the typhus- 
like diseases, Fletcher had observed that they were widely distributed 
across the warmer parts of the globe, from New York and Marseilles 
in the northern hemisphere to Adelaide in the southern. They com- 
prised, Fletcher argued, a list of names rather than a Hst of diseases: 
shop typhus, scrub typhus, tropical typhus, sporadic typhus, twelve- 
day fever, and many others. Plainly, some rational criterion for group- 
ing these maladies was needed. 

During the 1920s, J. W. D. Megaw of the Indian Medical Service 
had proposed classification according to arthropod vectors: (i) louse 
typhus; (2) tick typhus; (3) mite typhus; (4) typhus-like fevers trans- 
mitted by unknown vectors. Fletcher advocated a simpler scheme 
based on geographic location. "The typhus-like fevers fall into two 
distinct groups: a rural group and an urban group." Rural types in- 
cluded Indian tick typhus; tropical scrub typhus of Malaya, Mossman 
fever of Australia, Rhodesian fever, and possibly fievre exanthematique 
of Marseilles. The urban group was comprised of endemic typhus, 
shop typhus of Malaya, Sumatra, and Java, and typhus endemique 
benin of Toulon. 

Fletcher made a strong case for separating epidemic typhus itself 
from all the others. In contrast to the well-known contagiousness of 
classic typhus, he argued, the other diseases were all noncontagious. 
"A case of typhus is a matter of public concern," he noted, pointing 
out that no public health authority in any country quarantined cases 
of Brill's disease or murine typhus. Other investigators, especially 
Charles Nicolle, who had originally identified the louse vector of ep- 
idemic typhus, believed that the classic disease belonged to the same 
family as murine typhus. Nicolle proposed a "unity" theory of typhus, 
arguing that the endemic form of the disease, because of its association 
with rodents, must be an older form. Epidemic typhus he regarded as 
an "evolved" form of the endemic organism. 

The lack of agreement about the classification and nature of these 



154 



Rocky Mountain Spotted Fever 



diseases underscored both the vigor of the field and the Umitations of 
existing laboratory technique. Inability to grow concentrated quantities 
of rickettsial organisms in anything other than their arthropod vectors 
inhibited more direct study of the immunological relationships among 
the rickettsiae. The tiny size of rickettsial organisms obscured the 
details of their morphology. Rickettsial disease research, in which work 
on Rocky Mountain spotted fever was grounded, thus continued to 
be oriented toward the various typhus-like diseases, rather than toward 
the causative organisms themselves. 

Most interesting to Rocky Mountain spotted fever investigators were 
foreign reports of new tick-borne rickettsial diseases. During 1927 and 
1928 in Marseilles, France, an unusual typhus-Uke fever was reported. 
Unlike typhus, the rash of this fever extended to victims' faces, and a 
persistent "black spot" was identified as a possible point of infection. 
In 1930, French parasitologist Emile Brumpt, professor at the Faculte 
de Medicine in Paris, diagnosed the Marseilles epidemic as north Af- 
rican fievre boutonneuse— the disease Alfred Conor had described in 
19 10 in Tunis. In his laboratory, Brumpt transmitted this "Marseilles 
exanthematic fever" to man through adult ticks reared from nymphs 
obtained on dogs in Marseilles. Since ships traveled regularly between 
Marseilles and north African ports, Brumpt suggested that the disease 
had been transported across the Mediterranean in the bodies of stow- 
away ticks, and he proposed that the causative rickettsia be named 
R. conori after Conor.^^ 

Confirmation of fievre boutonneuse as a new tick-borne rickettsiosis 
stimulated comparative research with Rocky Mountain spotted fever 
on both sides of the Atlantic. In July 1932, Brumpt visited the Spotted 
Fever Laboratory in Hamilton, Montana, and collected infected ticks, 
which he took back to Paris. He received one injection of the Spencer- 
Parker vaccine, but he had such a severe reaction that he did not take 
the prescribed second dose. In February 1933, after returning to France 
and initiating his research, Brumpt fell ill. It was finally determined 
that he suffered from Rocky Mountain spotted fever, but diagnosis 
was difficult because he was in delirium and no previous case of spotted 
fever had been observed in France. Brumpt was transferred to the 
Hopital Pasteur and eventually recovered. 

At the university in Paris, Brumpt's illness produced a "considerable 
stir." Although he was probably infected through a wound in his hand 
during a necropsy on an infected guinea pig, rumors circulated that a 
"vial containing the ticks had been carelessly broken by a laboratory 
assistant, that the ticks had been scattered over the laboratory, and 
that Professor Brumpt had been bitten." Students refused to return to 



spotted Fever outside the Rockies 



155 



the building until all tick vials were destroyed and infected guinea pigs 
were killed. The press announced to the public that Rocky Mountain 
spotted fever could not spread in France "by reason of the climatic 
conditions," and although this argument may have had little value, it 
calmed the public mind. As soon as he recovered, Brumpt requested 
sufficient spotted fever vaccine to inoculate ten members of his lab- 
oratory staff.^^ 

On the western side of the Atlantic, NIH investigator Lucius F. 
Badger also studied the immunological relationship between Rocky 
Mountain spotted fever and fievre boutonneuse, which Americans 
came to call boutonneuse fever. Badger concluded that the diseases 
were immunologically identical, but shortly afterward, Gordon E. Da- 
vis and Ralph R. Parker at the Spotted Fever Laboratory in Montana 
reported that spotted fever vaccine did not protect against boutonneuse 
fever. They speculated that the European disease was less closely related 
to spotted fever than was another new tick-borne disease in Brazil. 

Identified in 1929 as Sao Paulo "typhus," this disease struck sixty- 
eight people between October 1929 and December 193 1. Like the 
Bitterroot Valley strain of Rocky Mountain spotted fever, it exacted 
a high mortahty: 80 percent of the victims died. Ecologically, Sao 
Paulo in the 1920s was similar to the Bitterroot Valley at the turn of 
the century. During the 1880s, Brazilian coffee planters, having 
watched the decline of slavery in South America, encouraged the im- 
portation of thousands of European immigrants, principally from Italy. 
This mass immigration had rapidly changed Sao Paulo from a small 
city to a thriving metropolis that strained its public health resources. 
By the 1920s many previously rural areas were becoming suburbs of 
the city. Human invasion of the habitat of several local ticks, most 
notably Amblyomma cajennense^ accounted for the apparently sudden 
appearance of the disease. In 1933, Sao Paulo typhus was identified 
in the nearby Brazilian state Minas Gerais, which had also experienced 
a recent population spurt.^^ 

Early research on Sao Paulo typhus was conducted by Jose Lemos 
Monteiro of Sao Paulo's Butantan Institute, a facility famous for re- 
search on snake venoms.^^ Lemos Monteiro showed the close rela- 
tionship between Rocky Mountain spotted fever rickettsiae and the 
rickettsial organism that caused the affliction in Sao Paulo. He asserted 
that Sao Paulo typhus was "a native disease" with its own individuality, 
and he proposed calling its causative organism Rickettsia brasiliensia. 
Emmanuel Dias and Amilcar Vianna Martins at the Oswald Cruz 
Institute in Rio de Janeiro and at the Ezequiel Dias Institute in Bello 
Horizonte supported Lemos Monteiro, proposing that the disease be 



156 



Rocky Mountain Spotted Fever 



called febre maculosa hrasileira in Portuguese, or Brazilian spotted 
fever in English. 

In 1933, however, a series of papers in Public Health Reports refuted 
the concept of a new^ disease. Parker and Davis at the Spotted Fever 
Laboratory found that convalescent serum from patients v^ith Sao 
Paulo typhus was protective against Rocky Mountain spotted fever, 
which indicated a close relationship between the organisms. A week 
later, Rolla E. Dyer stated that the two diseases were identical. Over 
the next few months, Parker and Davis published two additional papers 
concluding that the "essential identity of these typhus-like diseases 
appears to be well established."^^ 

More importantly, these studies directly affected residents of the 
stricken Brazilian towns, for they indicated that the Spencer-Parker 
vaccine should offer protection against Sao Paulo typhus. And, indeed, 
once the identity of the diseases had been confirmed, BraziHan scientists 
persuaded their government to attempt large-scale production of the 
vaccine at the Butantan Institute. Jose Lemos Monteiro and his assis- 
tant, Edison de Andrade Dias, traveled to Montana in the fall of 1933 
to study production methods and to appeal for a supply of vaccine 
until Brazil could produce its own. Although supplies were short in 
Montana, 1.5 liters of the vaccine were sent to Sao Paulo. 

While visiting the Spotted Fever Laboratory, Lemos Monteiro and 
de Andrade Dias had been routinely inoculated with spotted fever 
vaccine, Lemos Monteiro taking two doses and de Andrade Dias a 
single dose. In November 1935, however, when they began grinding 
ticks in Sao Paulo to manufacture the vaccine, both became infected 
with spotted fever. The Spencer-Parker vaccine they had received a 
year and a half earlier may have lengthened the incubation period of 
the disease, which was observed to have been long. Tragically, it did 
not save them: Lemos Monteiro died seven days after becoming ill, 
and de Andrade Dias survived for only five days. At the Spotted Fever 
Laboratory, Ralph R. Parker recorded these fatalities, noting that, 
ironically, the lot of vaccine on which they had been working displayed 
a high immunizing value. After this tragedy, Emmanuel Dias and 
Amilcar Vianna Martins took over the Brazilian vaccine program. Tick 
eradication methods for Sao Paulo were also investigated, but they 
proved disappointing, hence vaccination was adopted as the primary 
prophylactic measure. ^° 

In 1937 another virulent epidemic was reported from Tobia, Co- 
lombia, a narrow, rural, river valley community located near Bogota 
in the eastern range of the Andean highlands. Symptoms of victims 
and guinea pig reactions to inoculations with blood all pointed toward 



spotted Fever outside the Rockies 



157 



an infection of the Rocky Mountain spotted fever type, and rickettsiae 
were identified in guinea pig tissues. Furthermore, the arthropod vec- 
tors of all the major typhus-like diseases, including the tick that trans- 
mitted Sao Paulo typhus, were present in the valley. From July 1934 
to August 1936, sixty-five people had contracted the disease, and only 
three had survived — a mortahty rate of 95 percent. 

By the early 1940s, Tobia petechial fever, as it was called, had been 
unmasked as another focus of Rocky Mountain spotted fever in the 
western hemisphere. Luis Patino-Camargo, director of Instituto Fed- 
erico Lleras in Bogota, treated patients, amassed epidemiological data, 
and compared strains of the infectious agent against rickettsial strains 
in ticks obtained from Parker in Montana. In the course of this work, 
one of Patino-Camargo's countrymen. Hector Calderon Cuervo, be- 
came yet another martyr to laboratory-acquired spotted fever.^^ In 
1941, Colombian authorities requested a half-liter of the Spencer- 
Parker vaccine for the afflicted area. One health official wrote that 
when the first vaccinations were performed, "the local civil authorities 
were present and the Reverend Father Jose Antonio Rodriguez, who 
blessed the vaccine and gave a speech regarding the great benefits of 
this prophylactic medium and the interest which the National Gov- 
ernment has taken toward freeing the region of this deadly disease."^^ 

Even as Rocky Mountain spotted fever was being unveiled in these 
South American countries, certain aspects of the disease in the United 
States seemed to become more baffling. In 193 1, when spotted fever 
was identified in the eastern part of the nation, the NIH typhus unit 
noted that it killed about 25 percent of infected guinea pigs. In contrast, 
death was "the rule" for those infected with the Bitterroot Valley strain. 
Guinea pigs showed a scrotal reaction with the western strain, but it 
had been noted only once in those inoculated with the eastern strain. 
"With these differences in mind," Dyer, Badger, and Rumreich des- 
ignated the disease in the east "as the eastern type of Rocky Mountain 
spotted fever in contrast to the western type of the disease."^"^ 

Almost at once, Ralph R. Parker took issue with the suggestion that 
the disease occurred in two different forms. The problem, he believed, 
lay in the limited experience of most investigators with spotted fever's 
variations. 

Most textbook articles on Rocky Mountain spotted fever and a very consid- 
erable proportion of the papers by those who have studied spotted fever in 
and out of the laboratory are too highly colored by the fact that all have done 
most or all of their work with strains from the Bitter Root Valley. Not only 
is this true, but it is also true that the Bitter Root Valley strains with which 
they have worked have been particularly selected for virulence and scrotal- 



158 



Rocky Mountain Spotted Fever 



lesion-producing power. As a result, all of us, I believe, have become too much 
incHned to look upon high fever and scrotal lesions as being part of the typical 
symptomatology of Rocky Mountain spotted fever in guinea pigs. ... I have, 
however, had extensive opportunity to observe guinea pig reactions to strains 
of lesser virulence, not only from other western points, but also many times 
from the Bitter Root Valley. ... I know, therefore, that there is a marked 
difference in guinea pig reactions to different strains and even to the same 
strain at different times, and for that reason the differences which Drs. Dyer, 
Badger and Rumreich have noted do not to me seem to have the possible 
differentiating significance which they apparently do to them.^^ 

Parker also cited documented differences in the clinical manifesta- 
tions of the disease in humans throughout the western states. Because 
the eastern and western strains produced full cross-immunity, Parker 
argued that, barring other differences of which he was unaware, they 
were no more different than were those in Montana and in Idaho. 
"My personal opinion," he concluded, "is that we will find Rocky 
Mountain spotted fever very widely distributed in nature in the United 
States, and that possibly human cases are occurring over a much larger 
territory than that from which they have thus far been recognized. "^^ 

Although Parker's arguments were logical and grounded in personal 
experience, his superiors in Washington, D.C., believed that further 
investigations were required, especially by pathologists. At the NIH, 
Ralph D. Lillie took up the question. The thirty-five-year-old LiUie 
had taken both his undergraduate training and his M.D. at Stanford 
University, earning the latter in 1920. At Stanford he was influenced 
by William Ophiils, a noted pathologist and student of Johannes Orth, 
who in turn had studied under the pioneer cellular pathologist Rudolf 
Virchow. Highly respected, Lillie had collaborated with other NIH 
researchers on problems ranging from pellagra to chemical and phar- 
macological toxicology to infectious diseases. 

In 193 1, Lillie conducted autopsies on four victims of eastern spotted 
fever and studied histological material on a fifth. His comparisons to 
the western type of the disease were made not on direct observations 
but on published findings of the twenty autopsies done since 1897. 
From this limited number of cases, Lillie observed that certain differ- 
ences could be noted between eastern and western spotted fever. Bron- 
chopneumonia, he found, was more frequent in the eastern type and 
perhaps suggested a relationship to typhus, in which "pneumonias 
have often been seen." He also noted fatty changes in the liver, en- 
largement of the spleen, and scrotal gangrene as more frequent in the 
western type. Focal brain lesions, which Lillie found "constantly pres- 
ent" in the eastern cases, were never mentioned in the autopsy reports 
of western cases. These and other differences, most notably the more 



spotted Fever outside the Rockies 



159 



prominent cutaneous hemorrhages in western spotted fever, associated 
with "its more acutely fatal course," led him to conclude tentatively 
that the diseases were indeed different.^^ 

During the next eight years, only two pathological studies of eastern 
spotted fever cases were published, and none appeared on western 
cases. Lillie himself studied the disease in guinea pigs and in chick 
embryos. As epidemiological experience with the disease in the east 
accumulated, however, it became clear that geography had little rel- 
evance to spotted fever's severity. In 1935, E. R. Maillard and E. L. 
Hazen of the New York State Department of Health noted a 30 percent 
mortality rate among ten cases that had occurred in upstate New York 
between 1926 and 1934. By 1941 the NIH typhus unit and other U.S. 
Public Health Service investigators had isolated virulent strains of the 
disease in ticks on the east coast and strains of low virulence in the 
west. When mortality rates were compared over large areas in each 
region, moreover, there was virtually no difference.'^^ 

Two 1940 clinical studies of larger groups of patients also challenged 
the designations eastern and western types of spotted fever. Investi- 
gators working at Walter Reed General Hospital reported on seven 
cases that occurred between 193 1 and 1939. Eugene R Campbell and 
his collaborator Walter H. Ketchum concluded that they found "Httle, 
if any, clinical basis for differentiating" the two spotted fevers. The 
second study, conducted by Alfred L. Florman and Joseph Hafkenschiel 
of the Johns Hopkins Hospital, was based on six adult and fifteen 
pediatric patients. They reported a 23.8 percent mortality, close to the 
28.1 percent mortality for the western states compiled by the NIH 
typhus unit. Florman and Hafkenschiel also challenged Lillie's dis- 
tinction that cases of eastern spotted fever often had bronchopneu- 
monia whereas the western type did not. Only one of their twenty- 
one patients had bronchopneumonia. Scrotal necrosis was absent in 
Lillie's cases, but Florman and Hafkenschiel published a picture of 
this phenomenon in one of their cases. "It would seem," they con- 
cluded, "that severity of infection, rather than geography or vector, is 
of importance in determining the pathological picture. "^^ 

By 1940, Lillie himself had accumulated detailed pathological in- 
formation on fourteen new cases of spotted fever. "This additional 
material," he wrote in a definitive 1941 study on the pathology of the 
disease, "tends to amplify the picture of the disease process and clarify 
some of the apparent disagreements between the 193 1 report and the 
earlier reports based on cases occurring in the Rocky Mountain area." 
The differences noted in his 193 1 paper — bronchopneumonia and 
brain lesions in the eastern cases and scrotal necrosis and enlarged 



spotted Fever outside the Rockies 



161 



spleen in the western cases— were more closely related to the length 
of illness than to inherent differences. Patients dying within ten days — 
a more common occurrence in the Bitterroot Valley but documented 
also in the east— demonstrated scrotal gangrene, enlarged spleens, and 
the severely darkened rash that had evoked some of the earliest de- 
scriptions of the disease, "black measles" and "blue disease." In con- 
trast, all patients in whom the disease lasted more than twelve days 
exhibited brain lesions, more pronounced involvement of the heart 
and large vessels, and a tendency toward complications such as bron- 
chopneumonia. Reiterating a point from S. Burt Wolbach's 19 19 paper, 
Lillie emphasized that the fundamental lesion in spotted fever was 
found in the circulatory system, where Rickettsia rickettsii caused the 
endothelial cells to swell and even burst, resulting in occlusion of the 
small vessels or promoting the formation of blood clots. Tersely sum- 
ming up a decade of pathological research, Lillie ended the debate over 
the differences in the disease east and west: "It may be concluded that 
there is no essential difference in the lesions of Rocky Mountain spotted 
fever whether in the Rocky Mountain area or on the eastern seaboard 
of the United States.""^^ 

Coincidently with these laboratory studies, entomologists were ex- 
ploring a new tactic to control tick populations. In 1930, when Emile 
Brumpt identified boutonneuse fever in Marseilles, he had recom- 
mended two procedures to help control the disease. The first was not 
unusual: dogs should be bathed in an arsenical solution to kill ticks. 
Brumpt's second suggestion, however, was aimed at achieving biolog- 
ical control of ticks by exploiting natural host-parasite relationships. 
For some years he had studied a small insect, Ixodiphagus caucurtei, 
which burrowed into ticks and destroyed them from the inside. He 
now proposed that they be introduced into Marseilles to kill ticks by 
parasitizing their bodies. 

Brumpt's idea was not new— in the 1880s a famous and successful 
experiment in biological control had been carried out in California 
against a scale insect of citrus trees. In that instance, a small beetle 
imported from Australia had successfully parasitized the scale insect 
and effected complete control within two years. Based on this prec- 
edent, efforts to parasitize ticks had already been tried in the United 
States with mixed success. In 1926, Wolbach had acquired tick par- 
asites from Brumpt to experiment with biological control of the large 
dog tick population that plagued summer residents of islands off the 
Massachusetts coast. Released on the islands of Naushon and Martha's 
Vineyard, the tick parasites survived for three years, but their numbers 
annually diminished, and they failed to become established. The dif- 



Rocky Mountain Spotted Fever 



ficulty with utilizing such natural tick control methods lay in the fact 
that these insects were native to tropical and subtropical areas and 
did not thrive in colder climates. For some time, however, there was 
hope that some species of tick parasites might be adapted to the north- 
ern United States. One candidate was Hunterellus hookeri, prevalent 
in Texas and commonly called the chalcid fly."*"^ 

In Montana, Robert A. Cooley took up the question of whether 
either the French or Texas tick parasite could be used to reduce the 
spotted fever tick population. In July 1926 he obtained a supply of 
the French insects from Wolbach and later received Hunterellus hookeri 
through the U.S. Bureau of Entomology. By 1928, Cooley's assistant 
at the Hamilton laboratory. Glen Kohls, had reared over three hundred 
thousand of the French parasites. They were liberated in the Bitterroot 
Mountains to see if they would parasitize the spotted fever tick under 
natural conditions. 

As this project got underway, Cooley laid plans to travel to Africa, 
the original home of tick parasites. Believing that other parasites might 
yet be undiscovered, Cooley planned to search for new ones and to 
learn more about their natural habits. In 1927 he applied to the Rocke- 
feller Foundation for funding to make such a trip, but the foundation 
rejected the proposal as falling outside the narrow medical criteria for 
which they gave grants. Cooley raised the needed funds from the 
Montana State Board of Entomology, commercial firms, and a wealthy 
brother in New York, and in April 1928 he sailed for Africa."^^ 

Although Cooley found tick parasites in the province of Transvaal, 
South Africa, they did not adapt to the cold Montana climate any 
better than the French species, which had not survived the winter of 
1928-29 while he was gone. In 193 1, when Cooley retired from uni- 
versity teaching and joined the Spotted Fever Laboratory in Fiamilton 
as a staff entomologist, he began experimenting with a new method 
known as latent parasitism. Previously the insects had been released 
at the proper time to attack feeding nymphal ticks, but latent parasitism 
called for releasing the insects at a time when they would attack larval 
ticks. Theoretically, the parasites remained in the larvae as they molted 
into nymphs and there overwintered in a latent condition. Parasite 
development proceeded the next spring when nymphs found a new 
host. During the summer of 1932, Cooley tried this method, releasing 
Hunterellus hookeri parasites in Montana, Idaho, Oregon, and Col- 
orado. 

As the United States sank deeper into the Great Depression, Cooley 
waited anxiously for the spring of 1933, when he could check the 
results of his work. Curtailment of funds prompted by the Depression, 



spotted Fever outside the Rockies 



163 



however, made it impossible to determine the results of these releases, 
except in western Montana. These restricted studies revealed that at 
least some of the parasites had survived the winter. It was also clear, 
however, that in contrast to the situation in tropical climes, only one 
generation of parasites each year was likely in the Rocky Mountain 
area.'^^ 

By 1934 the constraints of the Depression forced an end to the tick 
parasite experiments. Cooley had showed that Hunterellus hookeri 
could survive under western conditions for two years if allowed to 
overwinter as latent parasites in unfed nymphal ticks. The work had 
not, obviously, produced the hoped-for effective and low-cost means 
to reduce the tick population that carried Rocky Mountain spotted 
fever. Like Lunsford D. Fricks's abortive sheep-grazing theory, how- 
ever, such a biological control system would have been a triumph had 
it proved workable. In 1934, Cooley transferred his attention to an- 
other long-term interest, building the Spotted Fever Laboratory's tick 
reference collection. In 1935 that collection contained eighty-three 
identified species and twenty-two unidentified species of ticks from all 
continents.'*^ 

The end of the tick parasite experiments also marked the beginning 
of the end of all government-sponsored tick eradication efforts in the 
Bitterroot Valley. State and county appropriations for the work had 
already been drastically reduced during the Depression. In 1935, 
A. L. Strand, w^ho had succeeded Cooley in 193 1 as secretary of the 
Montana State Board of Entomology, called a meeting with the U.S. 
PubHc Health Service, the U.S. Bureau of Biological Survey, the U.S. 
Forest Service, and "other interested parties" to discuss any practical 
way to reduce ticks over wide areas in Montana. Ralph R. Parker and 
others with experience in tick control measures offered very little hope 
that anything would work. During the Depression, men in the Civilian 
Conservation Corps camps in the Bitterroot Valley had been employed 
to collect ticks and assist in various tick control efforts. Parker argued 
that their efforts would have been better used in reforestation of mar- 
ginal land on the western edge of the Bitterroot Valley next to the 
mountains. After this meeting, organized tick eradication efforts in 
western Montana were suspended. The next few years brought ad- 
ditional checks on tick parasites and occasional bits of promising 
information about the ability of the insects to survive in cold climates. 
Ground squirrel eradication and some stock dipping were continued 
by individual initiative, but no further attempt was made to eradicate 
ticks from mountainous or marginal lands. ^° 

From the time its efficacy was first demonstrated, the Spencer-Parker 



Rocky Mountain Spotted Fever 



vaccine was embraced throughout the west as the principal defense 
against Rocky Mountain spotted fever. Because of the pecuHar nature 
of this tick tissue vaccine, however, long-term funding for vaccine 
production had never been resolved. The U.S. Public Health Service, 
which had funded vaccine development, hoped that other afflicted 
western states might pool resources with Montana to produce it, but 
all such requests had routinely been ignored.^ ^ As demand for the 
vaccine grew outside Montana, the state thus sought to shift the fiscal 
burden for future vaccine production to the federal government. 

Momentum for shifting responsibihty from state to federal shoulders 
increased in June 1930, when all three members of the Montana State 
Board of Entomology attended the Salt Lake City meeting of the 
western branch of the American Public Health Association. They were 
successful in having a study committee appointed, chaired by W. F. 
Cogswell, secretary of the Montana State Board of Health and pres- 
ident of the state board of entomology. Comprised of the state health 
officers of Wyoming, Idaho, Arizona, California, and Oregon, the 
committee met in Hamilton on 24 September 1930 and passed a 
resolution that the U.S. Public Health Service, through a congressional 
act, should take over the work of the Spotted Fever Laboratory, in- 
cluding the tick parasite research. 

The following month, Cogswell presented the resolution to the na- 
tional meeting of the association in Fort Worth, Texas. The president, 
A. J. Chesley, made particular mention of the spotted fever problem 
in his presidential address, and Surgeon General Hugh S. Cumming 
of the U.S. Public Health Service called a luncheon meeting of all those 
interested in the disease. Since one case of spotted fever had been 
reported in Texas and two in Nebraska, Cumming went on record in 
support of Cogswell by stating that spotted fever was a national prob- 
lem. After this, to no one's surprise, the annual meeting adopted the 
committee's resolution. Cogswell followed up with a well-organized 
lobbying campaign. He sent out a circular letter to all state health 
officers seeking support for the legislation and for an adequate ap- 
propriation. Thirty-nine representatives of state health departments 
pledged to work actively in the effort.^^ 

On Friday, 30 January 193 1, Senator T. J. Walsh of Montana in- 
troduced S. 5959, A Bill Authorizing the Purchase of the State Lab- 
oratory at Hamilton, Montana, Constructed for the Prevention, Erad- 
ication, and Cure of Spotted Fever, into the third session of the seventy- 
first Congress. In a speech accompanying the introduction of the bill, 
Walsh emphasized the danger of vaccine production and noted the 
increased demand from other western states. New York Senator Royal 



spotted Fever outside the Rockies 



165 



Copeland, a homeopathic physician with a strong record of supporting 
pubhc health measures, backed Walsh, citing as a precedent the transfer 
of the quarantine station at the port of New York to the federal 
government.^"^ 

The proposal also found support from Senator Hiram Bingham of 
Connecticut, who had initiated an inquiry about vaccine production 
at the urging of his state health commissioner, Stanley H. Osborn, a 
member of Cogswell's army of public health lobbyists. Bingham que- 
ried Treasury Secretary Andrew Mellon, in whose department the U.S. 
Pubhc Health Service was then located, about support for the Service's 
plans to take action against spotted fever. The senator pointed out to 
Mellon that cases known outside the Rocky Mountain region had been 
traced to the common dog tick, Dermacentor variabilis, which was 
plentiful east of the Mississippi River and thus a potential vector 
through which the disease might spread. Secretary Mellon replied that 
he had already approved a $35,620 increase in funds for spotted fever 
work in fiscal year 1932, a decision that augured well for the favorable 
consideration of Senator Walsh's bill.^^ 

As was customary for health-related legislation, Walsh's bill was 
referred to the Senate Commerce Committee, and its proponents 
stepped up their lobbying efforts. Prominent members of the General 
Federation of Women's Clubs contacted committee members and other 
key administration officials. Surgeon General Gumming kept a tally 
of letters received from members of Congress about the purchase of 
the laboratory. In addition to the expected letters of support from 
western states, members of the congressional delegations from Ala- 
bama, Ohio, Connecticut, and Maryland all wrote to praise the bill. 
Osborn next spurred Bingham into soliciting support from President 
Herbert Hoover, who the previous year had demonstrated an interest 
in public health matters by assisting the passage of a U.S. Public Health 
Service reform act and the Ransdell Act renaming the Hygienic Lab- 
oratory the National Institute of Health. Hoover was receptive, and 
his support provided the leverage needed for timely and favorable 
recommendations from the Budget Bureau and the Treasury Depart- 
ment, essential requirements for the passage of any bill.^^ 

So effective was the work of the organized proponents and so popular 
was the work of the laboratory that only one incident blemished the 
bill's forward march to passage in the Congress. A provision for Robert 
A. Cooley's tick parasite work prompted one congressman to write to 
the secretary of agriculture, asking if that work was not more appro- 
priately done under the auspices of the U.S. Bureau of Entomology. 
Echoing the decades-old question of the relation between professional 



mm'- 





spotted Fever outside the Rockies 



167 



entomologists and medical researchers, this issue arose just before the 
bill was to come before Congress. Perhaps lulled by the generally 
favorable response to the bill, Cooley and Ralph R. Parker were jarred 
by the news that the tick parasite research might be cut. Parker tele- 
graphed the surgeon general that the Montana state legislature had 
not appropriated additional monies for entomological work, assuming 
that the U.S. Public Health Service would take it over. Assistant Surgeon 
General Lewis R. Thompson replied that although the Service had not 
intended to take up the work, the surgeon general would allow it to 
be funded out of the spotted fever appropriation rather than see it 
discontinued. In addition, Thompson intervened with the secretary of 
agriculture, assuring him that if the bill passed, there would be no 
dispute along these lines. The secretary, settling the matter, wrote the 
inquiring congressman that he was in favor of the passage of the bill.^^ 

On 17 February, two weeks after its introduction, the bill was re- 
ported favorably out of committee without hearings and with only 
two minor changes in its language. Although it was not on the ap- 
proved calendar of the Senate, on 20 February, Senator Walsh asked 
unanimous consent for immediate consideration of the bill. Unanimous 
consent was required for any bill not already scheduled, and since the 
Senate was in the closing days of its session, the bill would have been 
delayed for some time had any senator objected. Walsh described it 
as "a matter of very great importance and particular urgency," noting 
that its consideration should not lead to a time-consuming debate 
because there was no opposition. Doubtless, the publication that very 
week of the NIH finding that spotted fever existed in Virginia and 
along the eastern seaboard enhanced the Senate's willingness to grant 
unanimous consent. The bill was read, the amendments accepted, the 
bill read a third time and passed without a recorded vote. On 27 
February the House of Representatives approved the bill, and President 
Hoover signed it on 2 March as Public Law No. 744. Two days later, 
Hoover also signed an implementing appropriations act that authorized 
$150,000 for spotted fever work during fiscal years 193 1 and 1932.^^ 

Unfortunately, this legislation was enacted just as the Great De- 
pression tightened its grip on the United States. Within a year, the 
effects of economic calamity became everywhere evident in federal 
programs. "Sad news is coming from Capitol Hill, daily," Roscoe R. 
Spencer wrote to Parker in March 1932. "It seems our salaries will 
be cut inevitably and I don't know what is going to happen to ap- 
propriations."^° Spencer's worst fears were confirmed in early 1933, 
as Frankhn D. Roosevelt prepared to assume the presidency. The 
budget Roosevelt inherited from Herbert Hoover proposed a reduction 



i68 



Rocky Mountain Spotted Fever 



of 25 percent for the U.S. Public Health Service. Rural sanitation work 
was to be virtually eliminated, cut from $150,000 per year to only 
$4,500, and the Division of Mental Hygiene's budget was to be cut 
by nearly 50 percent. Research programs were also hard hit. Although 
the maintenance appropriation of the NIH was slated to drop only 
about 25 percent, from $54,775 to $42,300, "field investigations" 
were to be slashed from $3 53,564 to only $54,000. This broad category 
covered a variety of research programs from cancer studies in coop- 
eration with Harvard University to research on scarlet fever, infantile 
paralysis, and sihcosis. The proposed budget also eUminated the ap- 
propriation for spotted fever work and stipulated that the Hamilton 
laboratory be shut down and the vaccine work discontinued.^^ 

Surgeon General Gumming countered the Treasury Department's 
proposal with one that preserved as many professional positions as 
possible and maintained research programs, if on a reduced scale. Of 
the work at the Spotted Fever Laboratory he wrote to Undersecretary 
of the Treasury Arthur A. Ballantine: 

If the government should discontinue this activity in the light of our present 
knowledge, the persons responsible for such action would in my opinion be 
morally responsible for the deaths which will occur as a result of the lack of 
this material. ... I may add that only a few days ago a" request was received 
from the Army for a large quantity of this material to be used for the protection 
of its forces in the field. The Service has been unable to persuade any other 
agency, official or non-official, to undertake the preparation of this material 
because of its danger." 

Gumming prevailed, and under Roosevelt's New Deal program, there 
was no further threat to the laboratory's existence. 

During this economically constrained period, Ralph R. Parker sought 
to keep his small group of researchers in the mainstream of scientific 
research by adopting practices already in place at the National Institute 
of Health. He initiated monthly staff meetings at which the work of 
each scientist was discussed. Recent journal literature was reviewed 
at meetings like the NIH's long-established Journal Glub.^"^ Under 
Parker's guidance, the laboratory expanded its work into other ar- 
thropod-borne diseases. Growth in the laboratory's tick reference col- 
lection and expertise of staff entomologists contributed to the facility's 
fame as a center for diseases of nature. In the 1933 outbreak of en- 
cephalitis in Saint Louis, Missouri, and the 1935 discovery of bubonic 
plague in rodents near Dillon, Montana, entomological experts from 
the laboratory cooperated with U.S. Public Health Service physicians 
in identifying the arthropod vectors and devising means to control the 
diseases. 



spotted Fever outside the Rockies 



169 



Tularemia, which had first been recognized as a problem in the 
laboratory animals used to test spotted fever vaccine, became another 
disease of nature in which laboratory staff developed expertise. Re- 
search in the early 1930s indicated that, in contrast to what had been 
believed, mild strains of tularemia could be demonstrated in nature. 
The laboratory experimentally secured mechanical transmission of the 
disease with the deer fly and black fly and demonstrated that the feces 
of some arthropods were infective. In 1934, two entomologists, Cor- 
nehus B. Philip and William L. Jellison, investigated an epizootic of 
tularemia among sheep near RingHng, Montana. Curiously, none of 
the ranch employees became infected, even though they hand-picked 
ticks from sheep and skinned those that died.^^ 

Two other newly discovered tick-borne diseases were also investi- 
gated at the laboratory. Tick paralysis, a mysterious disease that par- 
alyzed a victim's motor nerves, was found to be caused only by the 
bite of the female wood tick, Dermacentor andersoni. Believed to be 
caused by a toxin, the paralysis began in the legs and slowly ascended. 
If the tick was not removed before the paralysis reached the respiratory 
muscles, the patient died. Once the tick had been removed, however, 
the patient recovered rapidly. In 1926 a report received from Colorado 
launched a study of a disease that came to be called Colorado tick 
fever. By the early 1930s this tick-borne infection could be character- 
ized only as "a probable disease entity," but continuing reports con- 
firmed it as a viral malady having symptoms similar to those of spotted 
fever with a shorter, milder course and no rash. Usually there were 
two distinct periods of fever separated by a symptomless day or two.^^ 

In addition to these investigations, researchers at the Spotted Fever 
Laboratory discovered an entirely new rickettsial disease. During the 
summer of 1935, Gordon E. Davis, a bacteriologist, isolated a filter- 
passing agent from Dermacentor andersoni ticks brought in by a lab- 
oratory attendant, Lawrence Humble, in connection with the tick- 
collecting work of the Civilian Conservation Corps (CCC) camp near 
Nine Mile, Montana. The following year a similar agent was also 
found in D. occidentalis ticks from southwest Oregon, Cahfornia, and 
British Columbia. Initial investigation suggested that it caused a disease 
of wild animals, but in March 1936, Parker wrote the surgeon general 
that he and Davis were practically certain that the organism was the 
agent of a disease in man. This new malady, which caused headache, 
high fever, body aches and pains— in short, all the symptoms of known 
rickettsial diseases except for a widespread rash— was soon designated 
Nine Mile fever, and Herald R. Cox, a newly arrived bacteriologist 
whose work will be discussed more thoroughly in the chapter 9, took 



Rocky Mountain Spotted Fever 



up the study of the causative agent. By 1938, Davis and Cox had 
pubhshed a description of their work on this mysterious agent, and 
Cox went on to characterize it as a rickettsia, for which he suggested 
the name Rickettsia diaporica.^^ This new organism, it was discovered, 
was present in many lots of the Spencer-Parker vaccine, hence vaccine 
recipients were unwittingly inoculated against Nine Mile fever as well. 
Since the laboratory believed its vaccine to be free from contaminating 
organisms, however, this discovery caused great concern. 

The year before Davis and Cox pubhshed their description of the 
organism, in a twist of scientific fate, an AustraHan physician, Edward 
Holbrook Derrick, published an account of a mysterious disease with 
similar symptoms occurring among abattoir workers in Queensland. 
Derrick designated it Q fever, the Q for "query," since little was then 
known about the illness. His countryman and a distinguished virol- 
ogist, Frank Macfarlane Burnet, swiftly identified the agent as a rick- 
ettsia. By the end of the decade, investigators on both sides of the 
Pacific had confirmed that the two diseases were identical. The priority 
of the AustraHan name Q fever supplanted the designation Nine Mile 
fever for this disease, which later was found to exist around the globe. 
When the Q fever organism was classed as a separate genus from other 
rickettsia, it was named Coxiella burnetii after Cox and Burnet who 
had initially described \t7^ 

Such productive research at the Spotted Fever Laboratory during 
the Depression years was clearly secondary to and protected by the 
demonstratively useful production of Rocky Mountain spotted fever 
vaccine. During the early 1930s, the greatest demand for the vaccine 
came from the Bitterroot Valley and from Harney County, Oregon. 
In 193 3 requests for the vaccine increased considerably from the eastern 
states, and the laboratory forwarded approximately 10,500 cc to the 
NIH for distribution on the east coast. In addition, vaccine was needed 
by the CCC camps in western national forests. Because demand for 
the vaccine always outstripped supply, the U.S. Public Health Service 
ruled that the civilian population was entitled to first consideration. 
Only the Bitterroot Valley CCC camps were certain to receive the 
vaccine. To mitigate this problem, the corps allocated special funds in 
December 1933, and CCC personnel in the Bitterroot flagged ticks for 
the extra batch of vaccine. Since adult ticks alone were used, the yield 
was low: only 40.8 liters out of 123 produced met potency standards. 
Even so, this amount was adequate to protect personnel in all highly 
infected areas of the west.^^ 

In December 1934 this tenuous situation was strained when news- 
papers reported that the president might double the number of men 



spotted Fever outside the Rockies 




Demand for the Spencer-Parker vaccine always outstripped supply. Here 
bottles of vaccine await shipment, resting on orders in letters and telegrams 
from across the United States. (Courtesy of the Rocky Mountain 
Laboratories, NIAID.) 



in the CCC camps. By April 1935 ^^e rumor had become fact. Nearly 
two hundred new camps were scheduled, including two in the Bitter- 
root and a number of others near the northern Rocky Mountain spotted 
fever region where the need for vaccine was most urgent. Parker feared 
that the vaccine supply would be severely strained by these develop- 
ments, especially since the laboratory's budget never seemed secure. 
For fiscal year 1934, for example, the appropriation had initially been 
cut from $86,649 to $49,000. Eventually, an additional $17,000 was 
released, and the CCC had contributed $20,000 toward the special 
lot of vaccine for the camps. In fact, the growing demand from the 
corps probably helped to stabilize the laboratory's budget. For fiscal 
19355 $71,000 was allocated, with an additional $20,000 expected 
from the CCC.^^ 

Many western citizens also complained directly to their congressmen 
about inadequate appropriations for vaccine work, often prodded by 
newspaper reporters, who were always prepared to question the pri- 
orities of government.^"^ This rising demand for the Spencer-Parker 
vaccine was carefully documented by Ralph R. Parker, who attached 
copies of many of the letters to his monthly reports to the surgeon 
general. A physician in Prineville, Oregon, Parker noted, penned the 
following plea: "Can you let me have any amount of serum? Ticks 



172 



Rocky Mountain Spotted Fever 



awful bad and people panicky. Send if possible." Many isolated farmers 
and ranchers also earnestly sought the vaccine. "We are 50 miles from 
the nearest Doctor . . . and each time we ask there, they are always 
out of this serum and in the rare instances when some of our neighbors 
have been able to get it, the charge is $2.00 each," wrote R. S. Mefford 
from Decker, Montana. Nurses and druggists also requested vaccine 
to administer to persons far distant from physicians. Their pleas were 
in vain, because laboratory policy restricted vaccine distribution to 
physicians and state or local health authorities. 

In part, this policy was adopted to assure that vaccine recipients 
would be supervised by a physician in the event of untoward side 
effects, with the additional benefit that statistics on the vaccine's ef- 
fectiveness would be easy to collect.^^ U.S. Public Health Service policy 
was also influenced by the widely prevailing philosophy of the medical 
profession in the United States. Championed by the AMA, this view 
held that physicians alone should administer all such vaccines and 
collect a fee for the service from all who were able to pay.^^ The vaccine 
itself was suppHed by the laboratory at no charge. 

Bitterroot Valley residents especially resented this policy in 1935, 
when they were asked to pay for the vaccine after ten years of receiving 
it free while the Service tested its efficacy. A. C. Baker of Hamilton 
complained to Montana Senator B. K. Wheeler that "the poor people 
of this valley" should continue to be vaccinated at no cost. "You take 
a poor family that has from six to 10 children, to pay $1.00 per child 
would be a serious hardship. The consequences will be, that they will 
not take the vaccine and then you will see the death list grow this year 
from the spotted fever." Responding to the senator's inquiry about 
the matter, Parker noted that the Service had actually planned to 
discontinue free vaccinations in 1933 but "because of the general 
existing financial situation," free vaccinations had been continued for 
two additional years. He also pointed out that valley residents could 
travel to Missoula and receive the vaccine free from the county health 
officer and that local physicians in Ravalli County were scaling their 
fees and vaccinating without charge "the families of those who are on 
relief." Other Montana counties offered free health department cHnics, 
also, and during the 1940s, the Ravalli County health department 
instituted such a program. 

Other groups willing to pay a fee if only they could obtain the 
vaccine included physicians and hospital associations representing con- 
struction companies with large crews of men working in the field. 
Because of the limited amount of vaccine, Parker resisted sending lots 
to these people, believing that it was being used "to decrease com- 



spotted Fever outside the Rockies 



173 



pensation costs for construction companies employing common la- 
bor."^^ Parker finally asked the Service for guidelines on how the limited 
supply of vaccine should be allocated. Taking a somewhat more liberal 
view, Assistant Surgeon General Lewis R. Thompson, chief of the 
Scientific Research Division, summarized the Service's rationale: 

I believe the first principle that should concern us is to get the vaccine into 
the more dangerous areas first. Requests from such areas should be filled to 
a greater extent than in the less dangerous areas. Second, I believe that the 
people who deserve the first consideration are those whose work takes them 
into dangerous areas. I do not believe the city man has the same call upon us 
as the country man, even if he has a now and then exposure. Third, I do not 
think that we should favor Federal employees, although I can see that here 
and there you may find individuals or groups which have as much right, by 
reason of the nature of their work, as civilians. Fourth, I believe that the 
question of decreasing compensation hazards for construction companies 
should not be taken into consideration but that such cases should be weighed 
in the same manner as all others. ^° 

Fortunately for Parker, who remained the principal person besieged 
with pleas for more vaccine, empirical experience with vaccine pro- 
duction over the years had led to many improvements that increased 



TABLE 3. Production of Spencer-Parker Vaccine, 19Z8-1940 



Year 


Liters (gross) 


Liters (net) 


1928 


12.8 


* 


1929 


25.2 


* 


1930 


55.0 


* 


1931 


117.2 


* 


1932 


153.2 


* 


1933 


205.1 


* 


1934 


212 


171 


1935 


315.6 


248.4 


1936 


506.8 (360)** 


274 


1937 


591.2 (309.6)** 


462.4 


1938 


592.4 


362.9 


1939 


756 


495 


1940 


559 


515 



SOURCE: RML, Annual Reports, 1928-40. 

NOTES: The widest use of the vaccine was during this period. After 1940, both tick tissue and 
yolk sac vaccine were produced. Tick tissue vaccine was temporarily discontinued during World 
War II and never returned to prewar levels. In 1948, when Lederle Laboratories began producing 
yolk sac vaccine commercially, produaion of tick tissue vaccine ceased. 

* Information not given 

**In 1936 the laboratory began storing a portion of vaccine for use in future years. The figures 
given in parentheses represent the number of liters used during the year that were also manufactured 
during that year. 



174 



Rocky Mountain Spotted Fever 



the volume available for distribution. These advances, which v^^ere 
noted in chapter 7, enabled the laboratory to produce 205.1 liters of 
vaccine by 1933, an increase of 3,600 percent over the tiny amount 
produced in 1926, the first year in v^hich vaccine production had been 
attempted (see Table 3 for a summary of liters produced, 1928-40).^^ 
Another major step forward was the 1935 discovery that vaccine could 
be stored without loss of potency, thus allowing some reserve stock 
to be maintained. Even with such improvements, the process remained 
expensive. Each liter of the vaccine cost about $375 to produce. 

Although the Spencer-Parker vaccine was embraced by thousands 
of people as the only hope against Rocky Mountain spotted fever, 
Ralph R. Parker and the NIH typhus unit continued to search for a 
simpler, less dangerous, and cheaper method of vaccine preparation. 
The discovery that spotted fever existed in the eastern United States 
and in South America underscored the national and international sig- 
nificance of this quest. After the U.S. Public Health Service assumed 
full responsibility for producing spotted fever vaccine, the burden of 
developing any new method rested on its investigators. Although the 
Great Depression hindered an all-out attack on the problem, research 
at last proved fruitful. The discovery of this improved method and its 
broad applications to rickettsial disease research are the subjects to 
which we now turn. 



Chapter Nine 



Dr. Cox's Versatile Egg 

An active field of science is like an immense anthill; the individual almost 
vanishes into the mass of minds tumbling over each other, carrying 
information from place to place, passing it around at the speed of light. 

Lewis Thomas, The Lives of a Cell 



Rearing millions of ticks each year and converting them into Rocky 
Mountain spotted fever vaccine v^as a service for w^hich residents of 
infected areas w^ere profoundly grateful. Numerous people who grew^ 
up in Montana during the 1920s and 1930s recall Wixh wry affection 
the sore, red arms they dutifully endured each year in order to be 
protected from the dread disease.^ The danger, expense, and sheer 
awkwardness of making vaccine out of ground-up ticks, however, 
weighed heavily on laboratory staff members. Toward the end of the 
1930s, a new method for preparing spotted fever vaccine was developed 
that also proved applicable to other rickettsial diseases. It also per- 
mitted the development of a more discriminatory diagnostic test and 
opened the way to fundamental studies on rickettsial organisms. The 
discovery of this technique was informed by productive research on 
the filterable viruses, and its subsequent applications were hastened 
by the medical problems of World War II. 

It was clear that the key to a better vaccine was finding some medium 
other than ticks in which rickettsiae would thrive. The relatively new 
method of tissue culture held great promise for solving the problem. 
In this technique, small fragments of tissue, such as minced chick 
embryo, were placed in plasma, serum, or some other "natural" me- 
dium enhanced with nutrients. Strict asepsis was needed to prevent 
contamination, but, if properly maintained, the tissue culture would 
grow and could be inoculated with microorganisms known to multiply 
in the cultured cells. Because the nourishing media and the tissues often 
varied in composition, however, quantitative control was extremely 
difficult to maintain.^ In 1923, S. Burt Wolbach and M. J. Schlesinger 
at Harvard University experimented with tissue plasma cultures and 
were able to keep rickettsiae alive for four generations.^ Unfortunately, 



175 



Rocky Mountain Spotted Fever 




Ida A. Bengtson, the first woman 
on the professional staff at the 
Hygienic Laboratory of the U.S. 
Pubhc Heahh Service, 
investigated ahernative methods 
for producing spotted fever 
vaccine. In 1937 she reported 
that an acceptable vaccine could 
be produced with rickettsiae 
grown in tissue cultures. Her 
technique was shortly eclipsed by 
Herald R. Cox's simpler method 
of cultivating rickettsiae in fertile 
hens' eggs. (Courtesy of the 
National Library of Medicine.) 



the vaccine process required much more luxuriant grov^th of the rick- 
ettsiae than the developing technique was able to produce. 

A much simpler technique for cultivating the filterable viruses v^as 
discovered in 193 1 by Alice Miles Woodruff and Earnest Goodpasture 
at Vanderbilt University. They found that the chorioallantoic mem- 
brane of the developing chick embryo provided an ideal medium for 
the growth of the fowl pox virus. This membrane is one of several in 
chick embryos; the amniotic and yolk sac membranes are two others. 
The chorioallantoic membrane is located just beneath the shell of the 
egg, hence it was easy to inoculate and to observe any growth of the 
pathogen that occurred. Soon after Woodruff and Goodpasture an- 
nounced their method, other researchers identified a number of viruses 
that flourished on this membrane."* 

At the National Institute of Health, a senior bacteriologist, Ida A. 
Bengtson, joined the typhus unit specifically to explore various methods 
of cultivating Rocky Mountain spotted fever organisms. Having be- 
come the first woman on the staff of the Hygienic Laboratory in 1916, 
Bengtson completed work for a Ph.D. in bacteriology in 19 19 at the 
University of Chicago.^ Before taking up work on the spotted fever 
problem, she had distinguished herself in studies of anaerobic bacteria 
and the toxins they produced. She also identified a new variety of 
Clostridium botulinum, which caused a disease known as "limber- 



Dr. Cox's Versatile Egg 



^77 



neck" in chickens, and studied the etiology of trachoma, an eye disease 
whose causative agent was then suspected to be a rickettsia. In 1935, 
Bengtson and Rolla E. Dyer began experimenting with the Woodruff 
and Goodpasture technique. They eventually managed to cultivate 
spotted fever rickettsiae on the chorioallantoic membrane of chick 
embryos, but the stubborn organisms refused to grow in the quantities 
necessary for vaccine preparation.^ 

After these disappointing results, Bengtson turned back to standard 
tissue culture techniques, studying the results other investigators had 
achieved with a variety of tissue types. The combination that worked 
best, she found, contained modified Maitland media, minced chori- 
oallantoic membrane, and guinea pig tunica vaginaHs, the scrotal mem- 
brane in which rickettsiae were concentrated. Shortly thereafter, she 
reported that a vaccine could be made from spotted fever rickettsiae 
cultivated in this manner. "The amount of vaccine which may be 
prepared is sufficient to suggest this method of preparation as prac- 
ticable."" 

Bengtson's method, although not ideal, might have supplanted the 
tick tissue method, had not a serendipitous discovery intervened to 
revolutionize the preparation of all types of rickettsial vaccines. Before 
this scientific breakthrough is discussed, however, a digression is nec- 
essary to examine the political context in which it occurred, because 
this particular discovery might not have come so soon, if ever, without 
the beneficial stimulation of President Franklin D. Roosevelt's New 
Deal program. In 1935, just as Bengtson was beginning her work, 
Roosevelt's activist social planners were guiding the wide-ranging So- 
cial Security Act through Congress. Signed into law in August, the act 
not only provided for old age assistance and other welfare measures 
but also authorized the expenditure of large sums for public health 
work.^ Title VI provided $2 miUion annually for health research in 
the U.S. Pubhc Health Service. This intersection of public policy and 
medical research stimulated the work of federal investigators. They 
could purchase new equipment, undertake new projects, and, perhaps 
most importantly, hire young researchers for the first time since the 
Great Depression began. 

Passage of Social Security was anticipated with relish in the U.S. 
Public Health Service for some months before Congress voted on it. 
Inviting suggestions for ways to expand research must have been pleas- 
ant indeed for Service leaders, who had endured years of diminished 
budgets. In March 1935 Assistant Surgeon General Lewis R. Thomp- 
son, director of the Division of Scientific Research, received from Ralph 
R. Parker a long list of research projects that would be worthy of 



178 



Rocky Mountain Spotted Fever 



funding at the Spotted Fever Laboratory. An ambitious $17,540 com- 
parative study of typhus-like diseases was first on Parker's ' Vish Hst," 
follow^ed by an allocation of $9,000 to "study methods of improving 
the present spotted fever vaccine and to seek some simpler method of 
vaccine production."^ 

Enactment of Social Security also presaged major changes in the 
U.S. Public Health Service. Hugh S. Gumming, who had served as 
surgeon general since 1920, found President Roosevelt's New Deal 
more liberal than his personal conservative philosophy could support. 
In 1936 he retired and was replaced by Thomas Parran, who, during 
Roosevelt's tenure as governor of New York, had been granted leave 
from the Service to become New York state health officer. In 1937, 
Parran reorganized the research program of the Service, consolidating 
the Division of Scientific Research with the National Institute of Health. 
As a result, NIH's longtime director, George W. McGoy, who, Hke 
Gumming, was a conservative, was replaced by Lewis R. Thompson, 
director of the Division of Scientific Research and a strong New Deal 
supporter. 

In Montana the most noticeable change during this period was the 
laboratory's new name. Through January 1936 the faciHty was known 
popularly as the Spotted Fever Laboratory and officially as the Ham- 
ilton Station of the U.S. Public Health Service. In February it became 
the Rocky Mountain Laboratory (RML).^^ Soon other traditional cus- 
toms also disappeared. Parker had always prefaced his monthly reports 
to the surgeon general with the phrase "I have the honor of submitting," 
after which he surveyed general topics, often commented on personnel 
and on additions to the physical plant, and finally focused on specific 
research activities. By 1938 the older formalities and the highly per- 
sonal form of monthly reports gave way. Personnel and facilities reports 
were filed separately, and the monthly reports contained streamlined 
summaries of research projects. 

Most importantly for the spotted fever research program, the Title 
VI provisions of the Social Security Act enabled the Service to hire 
Herald R. Gox, a microbiologist whose primary duty was to search 
for a less dangerous, more efficient means to produce spotted fever 
vaccine. Born on 28 February 1907 in Rosedale, Indiana, Gox took 
his undergraduate degree at Indiana State Gollege in 1928 and earned 
a Doctor of Science degree in 193 1 at Johns Hopkins University with 
research in the filterable viruses. From 1932 to 1936 he was an 
assistant in Peter K. Olitsky's laboratory at the Rockefeller Institute, 
where, according to one eminent virologist, Gox "got a wonderful 



Dr. Cox's Versatile Egg 



179 




In 1937 Herald R. Cox discovered that rickettsiae would grown luxuriantly 
in the yolk sacs of fertile hens' eggs. This discovery revolutionized the 
production of Rocky Mountain spotted fever vaccine. It also provided a 
means to produce vaccines against epidemic typhus and other rickettsial 
diseases. (Courtesy of the Rocky Mountain Laboratories, NIAID.) 

training in doing experimental work with various viruses." He reported 
for duty at Hamilton on 31 May 1936.^^ 

For "the better part of two years," Cox experimented with flask 
cultures of tissues derived from chicken embryos and chorioallantoic 
membranes. He used a variety of nutrient media, "without a bit of 
worthwhile success." After offering his resignation to Parker and being 
told to keep trying. Cox had one of those happy accidents of science 
that solved the problem. In late February 1938 he temporarily ran out 
of the chorioallantoic membrane and embryonic chicken tissues needed 
to conduct one experiment properly. What he had immediately avail- 
able, however, was yolk sac membrane tissue, aseptically removed and 
stored in an Erlenmeyer flask. In order to proceed with his plans, he 



i8o 



Rocky Mountain Spotted Fever 



inoculated the yolk sac tissue with rickettsiae. Within a week, Cox 
found "literally thousands" of rickettsiae growing in the yolk sac 
cultures. "That night I was too excited to sleep," he recalled in a later 
memoir. His mind racing, he realized that flask culture was unnec- 
essary. "It would be so much simpler to inoculate fertile hens' eggs 
directly into the yolk sac area, through the air sac end of the egg," he 
reasoned. Since he lived close to the laboratory, Cox decided to try 
this new idea immediately. At four o'clock that morning, he went back 
to the laboratory and inoculated the first yolk sacs directly through 
the egg shell. 

After several repetitions of the experiment with uniformly successful 
results. Cox reported the breakthrough via the laboratory's April 
monthly report. When the news reached the NIH in Bethesda, however, 
RoUa E. Dyer was apparently not convinced. With some reHsh, Cox 
recounted Dyer's trip to Montana to inspect the new procedure. 

Dr. Dyer came into the lab at about 1:30 p.m. It was the first time we had 
ever met, and I soon learned that he was one that came immediately to the 
point in his speech and did not stand for any monkey business. The first thing 
that Dr. Dyer said to me was, "Cox, I don't believe a damned word in that 
recent monthly report of yours, in which you state that you are able to cultivate 
rickettsiae in great numbers in fertile hens' eggs, because Dr. Ida Bengtson 
and I tried for about 3 years to grow rickettsiae in fertile hens' eggs and we 
didn't have a bit of luck." I said, "Dr. Dyer, did you ever examine the yolk 
sac membrane tissue in those eggs to see if any rickettsiae were there?" He 
said, "No, we didn't." I said, "Well, that was your mistake, because that is 
where you would find the rickettsiae. Now, let's quit arguing and you sit down 
and look at these representative slides of spotted fever, epidemic typhus and 
Nine Mile fever, and then tell me what you think of them." Well, Dr. Dyer 
sat down and looked at slides for about lo-i 5 minutes. Then he turned around 
and said, "Well, I'll be, but you've convinced me. You surely have done what 
you stated you did." Then he stood up and shook my hand, as if to seal the 
bargain. 

It is difficult to overstate the impact of Cox's discovery on every 
area of rickettsial disease research during the next decade. As soon as 
he published his method, it was apparent that the long-sought means 
had been found to cultivate all types of rickettsial organisms not only 
easily but cheaply. Almost immediately, with two technicians, E. John 
Bell and Lyndahl Hughes, Cox went to work making experimental 
vaccines against spotted fever, epidemic typhus, and Q fever. They 
found that even the earliest ones satisfactorily protected guinea pigs. 
Since production required eggs instead of ticks, vaccine manufacture 
would no longer be tied to a geographical location where ticks were 
widely available. Further, the cost of production would drop dra- 
matically, so commercial firms could be expected to take over pro- 



Dr. Cox's Versatile Egg 



i8i 



duction of the Cox vaccine, as it came to be called. The cultivation 
of rickettsiae in eggs also made it unnecessary to stock thousands of 
laboratory animals in w^hich strains of the diseases w^ere previously 
maintained. Many other lines of research suddenly became fruitful, 
including metabolic studies and the concentration of antigens for di- 
agnostic tests and for the production of improved therapeutic immune 
sera. "The features that make the yolk sac technique of particular 
value," Cox himself noted in 1941, v^hen he accepted the American 
Association for the Advancement of Science's Theobald Smith Av^ard, 
"are its extreme simplicity and the ease w^ith v^hich cultures may be 
maintained v^ith a minimal risk of contamination."^^ 

At the same time that Cox was developing his yolk sac method, 
Hans Zinsser and his associates in the department of bacteriology and 
immunology at Harvard University School of Medicine were devel- 
oping an alternative method to culture rickettsiae. Like Ida Bengtson's 
attempts v^ith modified Maitland media, the Harvard group sought to 
utilize tissue cultures, but they chose spleen tissue on agar slants. By 
1939 they reported some success w^ith the method and described their 
vaccine production technique.^' Thus by the end of the decade, three 
new methods v^ere available in the United States for the culture of 
rickettsiae: Bengtson's modified Maitland media technique. Cox's yolk 
sac method, and Zinsser's agar slant approach. 

Over the next two years. Cox compared the practicality of his 
method v^ith Bengtson's, and researchers at the Lederle Laboratories, 
a division of the American Cyanamid Company, measured the im- 
munizing values and ease of preparation of the Cox vaccine against 
the agar slant tissue culture vaccine. With Bengtson's method. Cox 
pointed out, it wsls difficult to produce a vaccine of consistent potency. 
Technical difficulties w^ith the Maitland method, moreover, w^ould 
make large-scale production difficult. The Lederle group arrived at a 
similar conclusion about agar slant culture. In low doses, they found, 
the Cox vaccine protected guinea pigs better. "We have made large 
volumes of vaccine by both methods and are convinced that under the 
conditions necessary to produce vaccine in large amounts the yolk sac 
technic [sic] is also easier to carry out and much less costly in time 
and materials. "^^ 

By 1940, Cox's Rocky Mountain spotted fever vaccine was ready 
to be used experimentally in humans. Ralph R. Parker cheerfully in- 
formed the surgeon general that the vaccine appeared safe and that 
"likely" it w^ould "soon replace the tick-tissue product now employed." 
After September 1939, however, when war broke out in Europe, the 
peacetime focus on indigenous spotted fever gave way to concern about 



l82 



Rocky Mountain Spotted Fever 



A technician in the 1940s is shown harvesting yolk sacs from eggs infected 
with rickettsial organisms. (Courtesy of the Rocky Mountain Laboratories, 
NIAID.) 



the international wartime threat of epidemic, louse-borne typhus. Out- 
breaks of typhus were expected in Hungary and Romania, where 
thousands of Polish refugees had fled the German invasion. In order 
to test the efficacy of Cox's experimental typhus vaccine, forty liters 
were forwarded to five isolated Hungarian villages. A portion of the 
refugees received the vaccine while others were left unvaccinated as 
controls. When Germany invaded the Balkans, Hungary was absorbed 
into the Axis bloc, and, unfortunately, all records of the test were 
lost.i^ 

Although the threat of war loomed large in 1940 and 1941, the 
United States remained neutral in the conflict. Public health officials 
could make only contingency plans for dealing with what Surgeon 
General Thomas Parran called the "national defense emergency."^° 
Among those plans was a concentrated effort to improve the epidemic 
typhus vaccine prepared by Cox's technique, for any involvement in 



Dr. Cox's Versatile Egg 



183 



the hostilities would place U.S. military forces at risk of contracting 
the classic scourge of armies. Military strategists who evaluated pos- 
sible sites for a second front in Europe carefully weighed the danger 
of typhus in their dehberations. The disease certainly militated against 
the Balkans as an invasion site. "Typhus was accordingly looked upon 
as one of the great disease threats that must be nullified if the Army 
was going to achieve its aim of reducing disease incidence to a point 
at which it would finally become a minor casualty producer," wrote 
a U.S. Army physician in a postwar retrospective article. World War 
I delousing techniques — bathing and steam or chemical treatment of 
clothing— had proved at best to be only temporary. The magnitude of 
the perceived typhus threat, therefore, provided great impetus to re- 
search on the promising but unproven Cox vaccine. 

At the NIH in Bethesda, Maryland, Norman H. Topping, the new 
chief of the typhus unit, directed an intensive research program to this 
end. The son of an obstetrician. Topping had grown up in Los Angeles, 
where his family moved after his birth on 12 January 1908 in Flat 
River, Missouri. After taking his M.D. in 1936 from the University 
of Southern CaUfornia and deciding against going into private practice, 
the young physician chose to pursue a career in the U.S. PubUc Health 
Service. An internship in San Francisco was followed by duty rotations 
before Topping was assigned to the NIH in July 1937. He arrived just 
before the September class of young officers— the first new group to 
receive research training since the beginning of the Depression. For a 
short period. Topping worked on dental research, but when Rolla E. 
Dyer invited him to join the typhus unit, he enthusiastically took up 
the study of spotted fever and Q fever. In 1938, Topping's interest in 
combating these diseases became somewhat more than just an intel- 
lectual challenge. On 30 December he was admitted to Walter Reed 
General Hospital "because of his own diagnosis of Rocky Mountain 
spotted fever." Described by the attending physician as "a dejected 
man with a 'hangover' appearance" and a temperature of 103.8° F, 
Topping suffered with spotted fever for nineteen days but eventually 
made a complete recovery.^^ 

Beginning in 1939, Topping and his colleagues in the NIH typhus 
unit focused on evaluating and improving the Cox vaccine. They be- 
lieved that Cox's technique offered the most cost-effective method, but 
in initial tests the experimental vaccine proved insufficiently concen- 
trated to protect guinea pigs against large doses of virulent typhus 
rickettsiae. Because of this setback, the typhus unit felt impelled to 
evaluate vaccines made by techniques developed outside the United 
States. In 1930 a Polish investigator, Rudolf Weigl, had produced the 



i84 



Rocky Mountain Spotted Fever 



first of these vaccines, which was similar to the Spencer-Parker tick 
tissue vaccine for spotted fever. Weigl isolated individual Hce under a 
microscope and, with a tiny needle, inoculated them intrarectally with 
typhus-infected blood. Batches of these lice were then fed for a week 
or more on human volunteers who had recovered from typhus. Finally, 
Weigl excised the infective gut tissue of each louse and treated it with 
phenol. Tissue from fifty to one hundred lice was required to immunize 
a single individual. Although Weigl's vaccine was efficacious, it was 
hardly adaptable to large-scale production. 

Another approach to preparing a vaccine against the endemic form 
of typhus transmitted by fleas had been pursued by Hans Zinsser's 
long-time Mexican collaborator, M. Ruiz Castaneda. Announced a 
year before Zinsser's untimely death from leukemia in 1940, this vac- 
cine was made from the lungs of rats that had been infected intranasally 
with murine typhus rickettsiae.^^ Ruiz Castaneda's method of growing 
rickettsiae was simple, but it was suitable only for murine typhus 
vaccines. The rickettsiae of epidemic typhus did not multiply to any 
extent in rats. In 1940, however, two French researchers prepared a 
mouse lung vaccine against epidemic typhus fever that protected guinea 
pigs. Even this promising vaccine, wrote Norman H. Topping, had 
"several disadvantages when compared to cultivation of the rickettsiae 
in fertile hens' eggs." In most locaHties, animals were more expensive, 
the intranasal inoculation of animals with viable rickettsiae was an 
extremely dangerous procedure, and possible contamination of the 
vaccine with naturally occurring rodent diseases could not be elimi- 
nated as a hazard. 

Herald R. Cox's method, even with its limitations, thus appeared 
more promising than others available, especially after a Canadian 
investigator developed a technique that improved it significantly. James 
Craigie, a researcher in the Connaught Laboratories of the University 
of Toronto School of Hygiene, employed ethyl ether to promote sep- 
aration of rickettsiae from the tissue in which they were cultivated. 
His method depended on the fact that rickettsiae, like a number of 
viruses, such as poliomyelitis and vaccinia, and like many pathogenic 
bacteria, were repelled from the interface of ether-water mixtures, 
while insoluble tissue or medium constituents were selectively attracted 
to the interface. Ethyl ether had the additional advantage of being 
bactericidal and capable of rendering rickettsiae noninfective with great 
rapidity.^^ 

When the Japanese bombed Pearl Harbor on 7 December 1941, and 
the United States entered the war, bringing the vaccine into production 
for military use became imperative. On 1 1 December, Dyer and Top- 



Dr. Cox's Versatile Egg 



185 



ping, along with officials of the U.S. Army, U.S. Navy, and Division 
of Biologies Control at NIH, traveled to Toronto to study Craigie's 
ether separation technique. Thus was launched an intensive research 
effort to improve the vaccine by Cox in Montana, by the NIH typhus 
team in Bethesda, and by Harry Plotz's group at the Division of Virus 
and Rickettsial Diseases at the U.S. Army Medical School in Wash- 
ington, D.C. 

Cox had little luck, but the Washington and Bethesda groups made 
progress. Ida A. Bengtson found a way to increase the yield of rick- 
ettsiae from yolk sacs, and, with Topping, discovered that alum pre- 
cipitation increased the vaccine's ability to produce complement fixing 
antibodies. Topping and M. J. Shear discovered that a soluble antigen, 
which had previously been discarded, could be added to the vaccine 
to enhance protective power. Plotz and his colleagues at the U.S. Army 
Medical School also identified this antigen, almost simultaneously. 
Bengtson, Topping, and Richard G. Henderson demonstrated a toxin 
produced by the epidemic typhus organism in yolk sac cultures, an 
observation that permitted development of a mouse neutralization test 
for the vaccine. 

As the United States mobilized for war, the NIH typhus unit was 
pressed to define standard vaccine production methods, even though 
research was incomplete and the early experiments revealed that several 
approaches produced equally effective protection. In August 1942, 
Topping outlined the best method then known for producing epidemic 
typhus vaccine in a directive prepared for restricted circulation. He 
cautioned that further refinements might be forthcoming. With regard 
to the Craigie ether extraction method. Topping observed that it had 
"already been modified several times" and that as work progressed, 
further modifications would probably be necessary.^^ 

The tight control exercised over this and all other scientific publi- 
cations relating to typhus during the war clearly reflected the strategic 
importance of the research. At the NIH investigators were assigned 
publication dates in the Public Health Reports in order to provide 
documentation of their research for later peacetime career consider- 
ations. Virtually no paper on matters relating to military medicine was 
published openly; most were circulated in mimeographed form to 
Allied researchers working in the same field. 

Additional human trials of the improved vaccine were needed, and 
Topping worked with Rolla E. Dyer to locate an area in which typhus 
epidemics occurred frequently but which was less volatile than war- 
torn Hungary. In August 194 1 they arranged through the Pan American 
Sanitary Bureau, headed by former Surgeon General Hugh S. Cum- 



i86 



Rocky Mountain Spotted Fever 



ming, to test the vaccine on Indian miners in isolated villages in Bolivia. 
Unfortunately, the follow-up by an official of the Bolivian health de- 
partment w^as inconclusive. Another test of the vaccine was under- 
taken by Rockefeller Foundation researchers working in Spain, where 
an epidemic had struck ten thousand people. John H. Janney and John 
C. Snyder of the foundation hoped for a controlled study in Spanish 
prisons, but turnover in the prison population thwarted their plans. 
When Pearl Harbor was bombed, moreover, they were forced to in- 
terrupt their work to return home. On the basis of hmited evidence, 
Spanish observers believed that the vaccine did help to control the 
spread of the disease. Further evidence was gained when Snyder and 
four laboratory assistants, who had been vaccinated with the Cox 
material, contracted typhus in the laboratory and suffered exception- 
ally mild cases. 

With suggestive but not conclusive proof of efficacy, epidemic typhus 
vaccine prepared by Cox's method with various modifications went 
into wartime production. Spotted fever vaccine also continued to be 
manufactured with rickettsiae propagated in yolk sacs, and it benefited 
from the improved methods. Because Cox's spotted fever vaccine was 
so much simpler and cheaper to produce— and apparently at least as 
effective as the tick tissue product— the Rocky Mountain Laboratory 
ceased production of the Spencer-Parker vaccine in 1942 as an economy 
measure. Later, small lots of tick tissue vaccine were again produced 
because of reports that some recipients were allergic to egg proteins 
in the Cox vaccines. The number of people at risk of contracting spotted 
fever was small, however, when compared to the threat of typhus in 
military and civihan populations. Research on Rocky Mountain spot- 
ted fever thus "drifted to the side lines of activity" at the RML. Within 
the year, representatives of commercial firms were visiting the labo- 
ratory, seeking to learn how to produce typhus vaccine, and two 
national magazines featured the work in reviews of wartime diseases. 
Cox himself left Montana at the end of 1942 to accept the position 
of associate director, later director, of viral research at Lederle Lab- 
oratories.^^ 

During the war, the Rocky Mountain Laboratory, established in the 
remote Bitterroot Valley to produce a vaccine against what was con- 
sidered to be a local disease, literally became a national vaccine factory. 
In addition to typhus and spotted fever vaccines, the facility also 
produced yellow fever vaccine for the military.^^ The laboratory's stra- 
tegic importance was reflected in the extraordinary security mounted 
to protect it. Immediately after the Japanese attack on Pearl Harbor, 
two night watchmen were ordered deputized and additional ones were 



Dr. Cox's Versatile Egg 



187 





By the 1940s, the Rocky Mountain Laboratory had grown through the 
addition of several new wings and buildings. During World War II, the 
laboratory^ produced vaccines against typhus, yellow fever, and Rocky 
Mountain spotted fever. (Courtesy of the Rocky Mountain Laboratories, 
NIAID.) 



armed. Beginning on i January 1942, armed guards were placed on 
duty at all times. 

Rocky Mountain spotted fever proved to be a minimal problem for 
the military during the war. Only eighty-one cases occurred among 
U.S. Army personnel, and more than half of these were recorded during 
1943, when large numbers of troops were in training camps around 
the United States. Thirteen deaths among these cases produced a mor- 
tality rate of 16.05 percent— lower than the 18.89 percent national 
average recorded between 193 1 and 1946. Early in the war the army 
adopted a policy of limited vaccination, targeting only those personnel 
such as patrols and guards who routinely worked in tick-infested, 
endemic areas. In 1942 the RML provided enough vaccine to vaccinate 
twenty thousand military personnel. Because this amount appeared to 
be excessive, the quantity was reduced. Only ten thousand people were 
vaccinated in 1943 and just thirty-five hundred in 1944. In 1945, 
however, the U.S. Army required vaccine for sixteen thousand people 
because of the large number of prisoners of war housed in endemic 
areas. 



i88 



Rocky Mountain Spotted Fever 



Casualties from spotted fever did not occur among military personnel 
alone, of course. One wartime domestic infection was especially no- 
table because it contributed to expanded worker's compensation rights. 
In 1942 a Utah man engaged in outdoor work was bitten on his hand 
by "something," which he brushed off. A week later he was hospitahzed 
with a severe spotted fever infection, and he died shortly thereafter. 
Alleging that her husband's death was due to a tick bite suffered in 
the course of his work, the widow sued and was awarded compen- 
sation. His employer appealed this decision to the Utah Supreme Court, 
arguing that ticks almost never bit humans on the hand, hence the 
infection was more likely contracted during the victim's leisure time. 
The court, however, observed that the victim worked in or near tick- 
infested brush areas and that the sequence of events was consistent 
with the pattern of fulminating spotted fever. Because of this it could 
be inferred "that the deceased picked up the tick in the course of his 
employment," hence the compensation award to the widow was sus- 
tained.^^ 

The nation's attention and principal rickettsial research effort, how- 
ever, was focused not on spotted fever but rather against epidemic 
typhus, the greatest direct threat to Allied troops. Without attempting 
to do justice to the story of typhus in World War II— a subject that 
deserves its own fuller treatment— a brief survey of the administrative 
machinery and major results of typhus control efforts is in order. Most 
of the leading postwar investigators in spotted fever and other rick- 
ettsial diseases established contacts and gained experience in the cru- 
cible of war, and the focus of their efforts was this close relative of 
Rocky Mountain spotted fever. Many preventive and therapeutic mea- 
sures developed for typhus, moreover, were adapted for application 
against spotted fever. 

The threat of classic, epidemic typhus to U.S. military forces was 
first addressed in 1942 as the invasion of North Africa was being 
planned. There were reports of typhus cases among the populations 
of Algeria and Morocco and of increasing numbers of cases in Egypt. 
Because of this, leaders of the U.S. Army, U.S. Navy, and U.S. Public 
Health Service promoted the formation of a special commission to 
coordinate efforts for combatting it. On Christmas eve 1942, President 
Franklin D. Roosevelt signed the extraordinary Executive Order 9285, 
establishing the United States of America Typhus Commission. Sep- 
arate from other committees created to deal with the multiple medical 
and scientific problems of the war, the Typhus Commission was 
granted wide-ranging powers to protect U.S. troops against typhus 



Dr. Cox's Versatile Egg 



189 



wherever it occurred or even, in the words of the order, where it "may 
become a threat." In addition, it was empowered to prevent the in- 
troduction of typhus into the United States. Composed of represen- 
tatives of the U.S. Army, U.S. Navy, and U.S. PubHc Heahh Service, 
the commission was originally headed by Charles S. Stephenson, chief 
of the Preventive Medicine Service in the Bureau of Medicine and 
Surgery of the U.S. Navy, who reported directly to the secretary of 
war. Stephenson resigned in February 1943 because of illness, and in 
August 1943 his successor, Leon A. Fox of the U.S. Army Medical 
Corps requested transfer to a position as field director. Stanhope Bayne- 
Jones, also of the U.S. Army Medical Corps, then assumed the direc- 
torship, which he held until 1946, when the commission was dis- 
solved.^^ 

Because epidemic, louse-borne typhus occurred rarely in the United 
States, most miHtary physicians had never seen a case of the disease. 
In February 1943 the U.S. Army Surgeon General's Office sent a group 
of medical officers to Guatemala to observe an outbreak of suspected 
epidemic typhus. Since murine typhus was known to be present in 
Guatemala, and since it could be spread epidemically by lice as well 
as by fleas, it was originally unclear which type of typhus had stricken 
the area. Eugene P. Campbell and Robert Vought, physicians working 
for the Institute of Inter- American Affairs, another extraordinary war- 
time government organization, believed from epidemiological and clin- 
ical information that this was, indeed, classic, louse-borne typhus. 
Blood samples from several villages were sent to the U.S. Army Medical 
School, where both the Weil-Felix test and the newly developed com- 
plement fixation test confirmed their clinical diagnosis. "With war 
coming on," Campbell observed, "the lack of clarity and reHability in 
distinguishing endemic— mild, or flea-transmitted— typhus from the 
serious, epidemic, louse-borne infection was a great concern to us in 
the field."^^ With such abbreviated experiences, U.S. military physi- 
cians prepared to deal with expected epidemics, for much military 
action was anticipated in known typhus foci. 

By the time U.S. troops went into North Africa, all had received the 
Cox vaccine against typhus. During the course of the war, the U.S.A. 
Typhus Commission distributed vaccine to some 30 million people. 
Much was funneled through British organizations and through the 
health division of the United Nations Relief and Rehabilitation Ad- 
ministration, which combated epidemic diseases among civilians. 
Although typhus did attack civilians in war-torn areas, in prisons, and 
in the concentration camps in German-occupied areas, it proved to be 



190 



Rocky Mountain Spotted Fever 



of little consequence to the U.S. military effort. Between 1942 and 
1945 there were only 104 cases of epidemic typhus among U.S. military 
personnel and no deaths. 

Although this record might imply that the Cox vaccine had succeeded 
admirably, British and U.S. studies were inconclusive about whether 
the vaccine actually reduced incidence of naturally acquired typhus. 
On the other hand, all observers agreed that it was highly effective in 
reducing the case fatality rate."^^ A principal reason that typhus never 
seriously challenged vaccinated U.S. troops was the development of 
an effective insecticide, the widespread use of which stopped nascent 
epidemics among civiHan populations before they began. This chemical 
was dichloro-diphenyl-trichloroethane, more commonly called DDT. 

First produced in 1874, DDT was not discovered to have insect- 
kiUing powers until 1939, after which a wave of research was con- 
ducted on its potential as a means to kill disease-carrying lice and 
mosquitoes. Major federal agencies involved in this work included the 
Bureaus of Entomology and Plant Quarantine of the U.S. Departm.ent 
of Agriculture, the Division of Pharmacology of the U.S. Food and 
Drug Administration, and the National Institute of Health. The In- 
ternational Health Division of the Rockefeller Foundation also con- 
tributed to the effort, and all research was coordinated by the National 
Research Council and the Committee on Medical Research of the Office 
of Scientific Research and Development. Two earHer powders lethal 
to hce— MYL in the United States and AL-63 in England— had been 
used with some success, but neither proved to be as effective as DDT. 
When short-term preliminary tests, conducted primarily in an Orlando, 
Florida, laboratory and at U.S. Department of Agriculture laboratories 
in Beltsville, Maryland, indicated that DDT was nontoxic for humans 
or animals, the chemical was ruled safe— despite warnings from the 
Audubon Society — and adopted by the U.S. Army in 1943 as the 
standard agent to be used against lice."^^ 

Before the advent of DDT, the appHcation of insecticide to indivi- 
duals was a cumbersome, awkward, and time-consuming process. Peo- 
ple had to remove their clothes, which were then dusted by hand, with 
great care taken to apply the insecticide to the seams where lice often 
hid. The Rockefeller Foundation's typhus team, however, found that 
the new powder could be applied with a "blowing machine" to puff 
it under clothes without their wearers having to remove them. Not 
only was the method faster, but it was also accepted by even the most 
modest civilians. A curious side effect of the new chemical was its sale 
on the black market in many countries because it was thought to be 
an opiate. "These people could sleep after they got deloused," remarked 



Dr. Cox's Versatile Egg 



191 



Stanhope Bayne-Jones. "They thought that this was the best sleep 
producing drug that they had ever come across. '"^^ 

Three months after AlHed forces landed in Italy in September 1943, 
an epidemic of typhus in Naples provided the first true test of DDT's 
effectiveness. U.S. Army medical officers cooperated with officials of 
the U.S.A. Typhus Commission and with representatives of the Rock- 
efeller Foundation. They identified and isolated cases and dusted as 
many members of the civilian population as possible with DDT. A 
Rockefeller Foundation report on the dusting operation observed: 
"This system of rapid dusting without disrobing enabled the mass 
dusters to care for as many as 66,000 patrons a day. More than 
1,300,000 were treated in January [1944] alone — and Naples has a 
population of less than 1,000,000, which shows that some people 
came for more than one treatment. . . . The epidemic in Naples which 
might have taken thousands of lives collapsed with astonishing rapid- 
ity."^ 

The very success of DDT in controlling epidemics of typhus fore- 
stalled a large-scale evaluation of the Cox vaccine's preventive powers 
under wartime conditions. In contrast, the yolk sac technique for 
cultivating rickettsiae clearly proved itself as a means to produce the 
concentrated antigens necessary for developing a more sensitive di- 
agnostic tool for typhus and for Rocky Mountain spotted fever. Con- 
structing a useful laboratory test for any infectious disease depended 
on the availability of strong antigens that would react with antibodies 
in a patient's serum to cause clumping or some other visible reaction 
in a test tube. The necessary antigens were obtained by growing large 
quantities of a pathogenic organism. Before Cox discovered that rick- 
ettsiae would multiply luxuriantly in yolk sacs of the developing chick 
embryo, researchers were hampered by the limitations of cultivating 
them in their arthropod vectors. Laboratory diagnosis was thus re- 
stricted to the guinea pig infection test first pioneered by Howard 
Taylor Ricketts or to the Weil-Felix test developed in 19 16. 

Before the mid 1920s, the need for more sensitive tests had not 
appeared acute, because the geographical location of typhus-like symp- 
toms seemed to define their nature. Spotted fever was believed to be 
confined to the northwestern states. Typhus, initially viewed exclu- 
sively as a louse-borne disease, was thought to be absent from the 
United States, except for occasional outbreaks around New York, 
which were attributed to importation of the disease from Europe and 
thought to be self-hmiting. Brill's disease, viewed as a pecuHar, httle- 
understood manifestation of typhus in New York City, conformed to 
the larger pattern. In 1926, however, when Kenneth F. Maxcy described 



192 



Rocky Mountain Spotted Fever 



the endemic form of typhus existing in the eastern United States, this 
geographical scheme was disrupted. A second type of typhus required 
some means to differentiate it from the classic epidemic form. In 193 1, 
when the NIH typhus unit reported the existence of spotted fever in 
east-coast states, further impetus was given to the search for better 
diagnostic techniques for the rickettsial diseases. 

Throughout the 1930s, the Weil-Felix reaction remained the only 
serological test available to confirm chnical observations. Initially de- 
veloped as a means to detect epidemic typhus, the test was examined 
in 1923 by F. L. Kelly for its possible use as a diagnostic tool for 
spotted fever. Kelly's research indicated that no reaction was obtained 
with the sera of spotted fever patients. In 1928, however, LeRoy Kerlee 
and Roscoe R. Spencer reported in a paper published shortly after 
Kerlee died that the Weil-Felix test was indeed useful in spotted fever. 
Noting that Kelly had made only a few titrations and studied only 
nine cases, early in the disease, Kerlee and Spencer used the OX- 19 
strain of B. proteus to test sera taken at intervals from seven days to 
one year after disease onset. Their research showed that agglutination 
became more complete as the diseases progressed and that agglutinins 
persisted longer in patients suffering from spotted fever than in those 
with typhus."^^ 

Two years later, Spencer and Maxcy, who had used the Weil-Felix 
test extensively for diagnosis in typhus cases, repeated Kelly's earlier 
experiments with a larger number of spotted fever and endemic typhus 
cases, using sera taken late in the disease. They found that the agglu- 
tination reaction was different in spotted fever and typhus. Spotted 
fever produced agglutinins of broader affinities and greater variability 
than those produced by typhus. Although the two diseases were closely 
related antigenically, typhus and spotted fever were immunologically 
distinct. Neither disease afforded protection to recovered animals 
against inoculation by the other."^^ 

Since the serum of typhus patients agglutinated the OX- 19 strain 
of JB. proteus at high titers and that of spotted fever patients at low 
titers, the Weil-Felix test provided a rough mechanism to differentiate 
between the two diseases. As the only laboratory technique available, 
by the early 1930s it has been widely adopted in the United States to 
confirm clinical diagnoses. It was of no value early in the disease, of 
course, because the reaction depended on the increase of antibodies 
as the body fought off the invading organisms. It was also useless if 
the patient died before sufficient antibodies had been produced."^^ An- 
other major drawback was its ambiguity in mild or atypical rickettsial 
infections, those cases most difficult to diagnose clinically as well. 



Dr. Cox's Versatile Egg 



193 



Curiously, although guinea pigs were the principal animal model 
used in rickettsial disease research, their sera did not agglutinate in 
the Weil-Felix test."^^ Other signs of infection in these animals had 
therefore been studied for their uniqueness in particular diseases. Until 
the mid 1920s, sweUing of the scrotum in male guinea pigs had been 
considered diagnostic for infection with spotted fever, and lesions 
formed in the brains of guinea pigs indicated infection with epidemic 
typhus. After the identification of murine typhus in 1926, however, 
this simple scheme no longer sufficed. Murine typhus had also been 
shown to cause scrotal swelling in guinea pigs, and in 1933, Lucius 
F. Badger of the NIH typhus unit demonstrated that brain lesions in 
this laboratory animal were not limited to typhus infections but also 
occurred in Rocky Mountain spotted fever. To complicate the picture 
further. Badger reported that other infectious agents could produce 
similar signs as well. "The identification in the laboratory of an un- 
known strain of virus as one of endemic typhus or as one of spotted 
fever," he told a meeting of the American Society of Tropical Medicine, 
finally depended on the production of definite and complete cross- 
immunity with a known strain of the virus suspected.^° 

During the 1930s, Henry Pinkerton and George M. Haas in the 
Department of Pathology at Harvard University Medical School con- 
tributed one new tool to assist laboratory diagnosis of rickettsial dis- 
eases. Beginning with S. Burt Wolbach's observation that spotted fever 
rickettsiae were found in the nuclei of tick tissues, Pinkerton and Haas 
reported from their own studies that typhus rickettsiae multiplied in 
the cytoplasm of the cells but never invaded the nuclei. Spotted fever 
rickettsiae, regardless of how atypically the disease was manifest, grew 
sparsely in the cytoplasm but formed compact spherical colonies in 
the nuclei of infected cells. The Pinkerton-Haas criteria proved useful 
for laboratory studies and at autopsies of typhus or spotted fever 
victims. They were, of course, not appHcable in clinical diagnosis. 

By the early 1940s, Herald R. Cox's yolk sac cultivation method 
provided a means to produce the concentrated antigens necessary for 
developing a new test based on the phenomenon known as complement 
fixation. It had first been described in 1901, when Jules Border, a 
Belgian scientist, had observed that an ingredient in the blood, which 
he called "alexine" but is now known as complement, was used up 
or fixed to cells in antigen-antibody reactions. In 191 1, Benjamin F. 
Davis and William F. Petersen, associates of Howard Taylor Ricketts, 
studied the complement fixing capabiHty of spotted fever serum. They 
used tick eggs as well as the serum and macerated organs of infected 
guinea pigs as sources of antigens, but their results were inconclusive.^^ 



194 



Rocky Mountain Spotted Fever 



Over the next two decades, European researchers used alcohohc ex- 
tracts of organs from fatal cases of epidemic typhus as antigens to 
study complement fixation in that disease, but again, the results were 
unsatisfactory/"^ In 1936 M. Ruiz Castaneda first reported positive 
complement fixation for typhus fever serum mixed with suspensions 
of endemic rickettsiae obtained from the peritoneal washings of in- 
fected x-rayed rats/^ 

With the advent of Cox's easy method of growing rickettsiae, a 
sensitive complement fixation test was soon developed. At the NIH, 
Ida A. Bengtson and Norman H. Topping developed the test and 
evaluated its usefulness for differentiating rickettsial diseases at the 
same time that they were attempting to improve the Cox vaccine. "The 
question of differentiation is of special importance," they noted in a 
1942 paper, "in those sections of the country where both endemic 
typhus and Rocky Mountain spotted fever occur, as in the eastern and 
southeastern sections of the country." Their studies showed that the 
complement fixation test was superior to the Weil-Felix test according 
to four key criteria. First, the complement fixation test furnished ev- 
idence of rickettsial infection earlier than the Weil-Felix test in 23.9 
percent of human sera tested. Second, it was superior because the 
complement fixation reaction persisted longer than did the Weil-Felix 
reaction. Third, low titers were significant in the complement fixation 
procedure. Finally, spotted fever sera tested negative nearly all the time 
against typhus antigens in the complement fixation test, while they 
often gave a false positive Weil-Felix reading.^^ 

Harry Plotz, Kenneth Wertman, and their collaborators at the Di- 
vision of Virus and Rickettsial Diseases of the U.S. Army Medical 
School in Washington, D.C., confirmed the NIH group's findings, using 
rickettsial antigens made by the agar slant method. Sera from two 
patients whose symptoms were confusing tested clearly positive for 
spotted fever and clearly negative for typhus. Further studies comparing 
the complement fixation test to the standard method of observing 
guinea pig reactions also produced evidence of the test's superiority. 
"Irrespective as to whether the guinea pig develops evidence of disease 
as expressed by a febrile reaction or scrotal swelling, or an inapparent 
disease without these reactions," they wrote in a 1946 paper, "specific 
complement fixing antibodies develop in early convalescence. The use 
of the complement fixation reaction, likewise, permits the detection 
of those animals that represent missed infections or those that develop 
fever from nonspecific causes. The use of the complement fixation 
method for strain identification is specific, rapid and inexpensive."^^ 

By the end of the decade, the complement fixation test had joined. 



Dr. Cox's Versatile Egg 



195 



if nor supplanted, the Weil-Felix test as a major diagnostic tool in 
rickettsial disease studies. Unfortunately, reagents for both tests were 
available only from a handful of laboratories, principally those of the 
NIH, the RML, and the Division of Viral and Rickettsial Diseases of 
the U.S. Army Medical School. Joseph E. Smadel, who was on the 
staff of the last-named institution, observed in 1948 that, even with 
the new tests, it still took ten days to three weeks to identif)^ rickettsia 
and that such work required the maintenance of a "museum of in- 
fectious agents" as well as "stocks of known antigens, antiserums and 
immune animals. "^'^ Physicians or pubhc health workers mailed sam- 
ples of blood to the laboratories and waited the requisite time for the 
results. 

Furthermore, scientific efficiency could be thwarted by nature or by 
human error at any link in the chain from patient to laboratory. The 
harsh Montana winter, for instance, occasionally interfered with anal- 
yses of blood samples sent to the RML. "The post office sometimes 
left mail sacks out on the platforms in minus thirty degree weather," 
recalled David B. Lackman, former chief serologist at the RML. "Blood 
specimens in the sacks froze at that temperature," producing an un- 
usable "syrupy mess." Physicians were encouraged to centrifuge blood 
specimens to remove the solid cells before mailing, he also noted, but 
many lacked the equipment or expertise to prepare the specimens in 
this manner. By the 1950s, however, commercial firms were manu- 
facturing rickettsial antigens, which facilitated the establishment of 
additional state or regional diagnostic laboratories. ^° 

The development of the complement fixation test, coupled with 
decades of experience with rickettsial diseases, made short work of 
identifvang a completely new rickettsial disease that appeared in Feb- 
ruarv' 1946. This malady was first described as a separate clinical entity 
among residents of an apartment complex in Kew Gardens, New York. 
It was named rickettsialpox to indicate that it w^as caused by a rick- 
ettsial organism and that it had initially been misdiagnosed as mild 
chickenpox. Charles Pomeranz, a local exterminator and amateur en- 
tomologist, alerted New York health authorities to the possibility of 
some sort of arthropod-borne disease after he found mite-infested mice 
m the apartment-complex basement. When New York investigators 
called on the U.S. Pubhc Health Service for assistance, Robert J. Hueb- 
ner and his colleagues in the Division of Infectious Diseases at the NIH 
and William L. Jellison, entomologist from the RML, joined in the 
collaborative effort. They isolated, described, and classified the etio- 
logic agent as a hitherto unknown rickettsia of the spotted fever group. 
Because the organism was found to inhabit the mite Allodermanyssus 



Rocky Mountain Spotted Fever 



sanguineus, a parasite of the house mouse, they named it Rickettsia 
akari, akari meaning "mite." Epidemiological research determined that 
the disease was contracted wherever mites had access to human living 
areas. In the case of the original apartment complex, the mites climbed 
up a central incinerator chute and infested the carpeting in apartments, 
thus rendering young children especially susceptible. In sharp contrast 
to the decades it took to understand spotted fever and the centuries 
during which epidemic typhus remained a mystery, the complete pic- 
ture of rickettsialpox was elucidated within eight months. 

Shortly before this triumph of laboratory investigation, however, 
another mysterious disease had eluded clarification. In 1942 and 1943 
there were "mass outbreaks of an apparently new clinical syndrome" 
at Fort Bullis in Texas that came to be called Bullis fever. It resembled 
a rickettsial disease, especially Q fever, and it was linked to a tick 
vector, but no immunological relationship between it and any known 
rickettsiosis could be conclusively demonstrated. Since no further cases 
occurred, investigation was halted, and, to the present, Bullis fever 
remains an unexplained mystery. 

Herald R. Cox's spectacularly successful method of growing rick- 
ettsiae in yolk sacs had been discovered in the search for a better 
vaccine against Rocky Mountain spotted fever. Two of its most im- 
portant consequences were the epidemic typhus vaccine that protected 
U.S. troops during World War II and the development of the comple- 
ment fixation test. Although it was clearly an advance over the culture 
of rickettsiae in ticks and in lice. Cox's technique was not without its 
Hmitations. Yolk sac vaccines did not provide complete protection 
against contracting rickettsial diseases, although, fike the Spencer- 
Parker vaccine, they did mitigate the course of the diseases. The more 
sensitive complement fixation test, moreover, shared one major weak- 
ness with the Weil-Felix test: both were diagnostic only when antibody 
levels rose during the course of the illness. Neither was of value at the 
time a patient first became ill. For more than three decades after Cox's 
discovery, however, his method remained the standard procedure for 
producing spotted fever vaccine, and the complement fixation test 
stood as the diagnostic tool of choice for rickettsial diseases. With the 
versatile egg. Cox accompHshed his goal, freeing vaccine production 
from the danger and expense entailed in the tick tissue method and 
opening wide new horizons for research on rickettsiae when World 
War II ended. 



Chapter Ten 



Spotted Fever Therapy, 
from Sage Tea to 
Tetracycline 

Many methods of treatment have been advised and employed in the 
attempt to cure this disease. They run the gamut of the Pharmacopoeia 
from sage tea to quinine and they have returned to that tacit admission of 
ignorance, "good nursing and symptomatic medication." 

William Colby Rucker, 19 12 



"The desire to take medicine," wrote William Osier of the Johns 
Hopkins University School of Medicine, "is perhaps the greatest feature 
which distinguishes man from animals."^ Whether folk remedies, pat- 
ent medicines, or compounds from orthodox pharmacopeias, all sorts 
of pills, powders, Hquids, and potions have been ingested by victims 
of disease in their quest to cure their sufferings. They have also sub- 
mitted to being bled, purged, vomited, and sweated. They have extolled 
water, hot or cold, placed their trust in injections or faith healers, and 
succumbed to the promises of quacks. Those people unlucky enough 
to contract Rocky Mountain spotted fever were no different. Because 
this disease was not identified until after the bacteriological revolution, 
however, the search for an effective therapy against it was infused with 
the positivism that has characterized twentieth-century medical science. 
Early spotted fever investigators were inspired by the dramatic cures 
discovered for diphtheria and tetanus and hoped for a similar break- 
through. None expressed hopelessness even as therapy after therapy 
failed to elicit a response. 

Unhke many diseases known for centuries, spotted fever was never 
generally viewed as a manifestation of God's wrath against sinners.^ 
Even before the tick-borne nature of spotted fever had been established, 
the disease was not considered contagious, and its victims were thus 
spared long quarantines like those that confined diphtheria and small- 



197 



198 



Rocky Mountain Spotted Fever 



pox patients. The history of spotted fever is different in this sense from 
air- or water-borne diseases, which often inspired widespread fear of 
frequenting pubHc places and generated antagonism against groups 
rumored to be the source of the disease. FaUing property values in 
infected areas and agitation against the establishment of a laboratory 
in the noninfected district did indeed cause unrest in the Bitterroot 
Valley. Spotted fever's geographical limitation to specific areas and its 
certain Hnk to ticks, however, precluded a sense of national peril against 
an unknown terror. Unhke the disease itself, the optimism of scientific 
medicine was contagious— from the beginning of scientific inves- 
tigations in 1902, people at risk in the Bitterroot Valley were con- 
vinced that research would eventually produce a therapy for their dread 
disease.^ 

Like the researchers who had preceded him, Thomas B. McClintic, 
the U.S. Public Health Service investigator who lost his hfe to spotted 
fever in August 19 12, examined potential cures for the disease. During 
the fall and winter of 1911-1912, while he worked in Washington at 
the Hygienic Laboratory, McClintic decided to investigate the thera- 
peutic potential of arsenical compounds. Treatment with these sub- 
stances had received a boost in 19 10, when Paul EhrHch introduced 
the arsenical he called Salvarsan as the first effective specific against 
the trypanosome of syphiHs. Not surprisingly, arsenic compounds soon 
were widely employed by physicians hoping that they might also be 
a "magic bullet" against other diseases. McCHntic, moreover, had 
recently learned from a Stevensville, Montana, physician that two 
spotted fever victims recovered after receiving sodium cacodylate, an 
antimalarial arsenical. His research with arsenicals, he noted, was 
theoretically based on "some indications pointing to the infection of 
spotted fever being protozoal in character." He thus chose to treat 
guinea pigs and rhesus monkeys with those arsenicals known to have 
a toxic effect on protozoan organisms."^ 

In addition to sodium cacodylate, he tried Salvarsan itself and hex- 
amethylenamine, a urinary tract bactericide known by its trade name, 
Urotropin. In order to test both the therapeutic and prophylactic pow- 
ers of the drugs, he administered doses to some of his experimental 
animals at the time they were inoculated with spotted fever. Usually, 
however, treatment began when the temperature of the animal began 
to rise. His results were "by no means" encouraging. "In fact," he 
wrote, "the administration of the drugs seems, on the whole ... to 
have hastened the death of most of the animals that were treated."^ 

McClintic's successors experienced similar frustrations. In 191 8, 
S. Burt Wolbach reported to the chairmen of the Montana State Boards 



spotted Fever Therapy 



199 



of Health and Entomology that he had conducted experiments on the 
therapeutic value of an antimony compound with negative results. 
Like McClintic, he observed that the hoped-for therapy actually had 
"a deleterious influence" and accented the vascular lesions in exper- 
imental animals. During the 1920s, Roscoe R. Spencer worked with 
salts of bismuth. In his 1923 annual report, he Hkewise concluded that 
these "chemotherapy experiments . . . have yielded no striking results."^ 

If these researchers sought a magic bullet that would selectively kill 
spotted fever organisms, others adopted what might be described as 
the shotgun approach of internal antiseptics. In 1924, H. P. Greeley, 
a physician from Madison, Wisconsin, speculated that "tick fever" 
might be more responsive to intravenous medications "because of its 
pathology." Greeley's logic, based on his knowledge that spotted fever 
attacked the capillaries, led him to treat a twenty-eight-year-old woman 
by injecting 20 cc of a i percent solution of Mercurochrome-220 
soluble intravenously. "Within an hour," he noted, "there was a severe 
chill, and following it the temperature rose to 104.8° F. Within six 
hours, the muscular pains and soreness began to leave." Although he 
admitted that one case did not prove his argument, he called for further 
trials of the chemical.^ 

Greeley's logic was characteristic of the type that underlay many 
spotted fever drug tests. If a drug was known to be efficacious for a 
disease having some symptoms in common with spotted fever, it seemed 
reasonable to test it. Such was the case in 1926, when a Dr. Henline 
suggested that Ralph R. Parker try Caprokol, the trade name for 
hexylresorcinol, another urinary tract antiseptic also used against 
hookworms and roundworms. Since kidney failure sometimes accom- 
panied spotted fever, Parker observed that it might "be worth while 
to try this out." Similarly, L. C. Fisher of the Department of Medicine 
of the University of Minnesota reasoned that the nature of the vascular 
lesions and the localization of the virus in the endothelium suggested 
that spotted fever might respond to intravenous chemotherapy. Im- 
pressed by British reports that "various colloidal substances" effec- 
tively modified the course of experimental typhus if given early. Fisher 
tested new drugs of this type: "Germanin (Bayer 205), metaphen, 
triphal (organic gold compound), and tryparsamide." None proved 
any better than earlier drugs in protecting guinea pigs against spotted 
fever. ^ 

Whenever scientific progress seems thwarted at every turn by the 
mysteries of disease, folk and quack remedies enjoy a surge of pop- 
ularity.^ The failure of medical science to uncover an effective cure for 
Rocky Mountain spotted fever encouraged many people to take ther- 



200 



Rocky Mountain Spotted Fever 



apy into their own hands. Unorthodox and quack treatments, based 
primarily on the post hoc, ergo propter hoc fallacy, abetted by the 
fear of an uncontrollable danger, and nearly always promoted with 
bold promises backed up with the mere pretense of evidence, took 
many forms. In 191 6, for instance, a Dr. Fox of Arco, Idaho, claimed 
to have discovered a "mixture of medicines which thru actual tests 
already made shows that it will abrupt a case of Rocky Mountain tick 
fever in five days." Dr. Fox based his claim to efficacy on the fact that 
five spotted fever victims recovered after taking his unnamed mixture. 
Patient number six may not have been so lucky, for nothing further 
was heard of Dr. Fox and his remedy. 

Advocates of other proposed therapies clothed their claims in the 
findings of bacteriology, promoting their products as "germ killers." 
In 1 94 1, one such product, manufactured by a family in Forest Grove, 
Montana, and known only as "the remedy," was sent to the Rocky 
Mountain Laboratory for testing. "The remedy is a Hquid," wrote 
Martin J. Elam in his accompanying letter. Because it contained "sev- 
eral ingredients, one being a poison," he instructed, it was "to be 
applied externally." Claiming that his nostrum was "an efficient germ 
killer," Elam asserted that it had cured his friends and neighbors of 
"blood poisoning, pink eye, insect stings and bites, infected tick bites," 
while having "no harsh effect on sores or the mucus membrane."^ ^ 

An even longer list of diseases was purportedly cured by a patent 
medicine similarly marketed as an external germ killer. Sold by the 
Triangle Drug Company in Edgerton, Wyoming, the C.Y.T. Tick Bite 
and Blood Poison Remedy was certified as effective for blood poison, 
snake bite, tick bite, toothache, gout, eczema, bunions, frostbite and 
chilblains, barbers' itch, ringworms, carbuncles, boils and warts, in- 
growing toenails, rusty nail punctures, and bee and insect bites. Such 
a wonder drug deserved exceptional advertising, and its handbill un- 
abashedly proclaimed C.Y.T. to be "The Greatest Discovery of the 
Twentieth Century for Men, Women, and Children." A separate page 
was required for the large number of testimonials from happy cus- 
tomers. Adopting the cautionary style of orthodox medicine, C.Y.T.'s 
handbill writers featured the word poison in large letters, gave direc- 
tions for the user "to rub in some vaseline or some good grade cold 
cream" after applying, and included this admonition in boldface type: 
"Do not apply after the inflammation and pain has been stopped." 
John A. Anderson, president of Triangle Drug Company, sent a bottle 
of the remedy to the RML for testing. Anderson believed that labo- 
ratory tests would show that C.Y.T. would "kill the virus of Rocky 
Mountain Spotted Fever, if used in time. We advise applying the med- 



spotted Fever Therapy 



20 1 



icine as soon as the patient has been bit by a tick, not waiting to see 
if he has been bit by an infected or a non-poisonous tick and in such 
cases results have been excellent." 

Older beliefs in the commonality of all diseases also contributed to 
therapies proposed for spotted fever. Humoral theory, for example, 
held that an imbalance in body humors caused disease. Blood was one 
essential body humor. Since spotted fever rickettsiae had been dem- 
onstrated in blood, and since syphilis was widely known as "bad 
blood," it is not surprising that the two might be linked. In 1938 an 
Idaho man who styled himself a "Dr of Naturapthie" and a twelve- 
year veteran cowboy in Wyoming, Colorado, and Idaho, claimed that 
"Spoted [sic] Fever is the (3rd) stage of Syples [sic] No Person who is 
free from Syphlectic Blood will Take Spoted Fever."^^ 

A Wyoming woman, who claimed she had "the right to M.D." but 
did not practice, combined humoral theory and folk wisdom with 
some simple chemistry. Arguing that the tick "is not more poisonous 
than others of its nature, except when it has been feeding on the carrion 
of sheep or other decayed flesh," she advocated treatment for a tick 
bite more commonly recommended for snake bites: "By saturating the 
saliva with tobacco, any friend may with impunity make suction over 
the wound by the mouth." She also recommended that the victim 
follow this treatment by using ammonia both externally and internally, 
since "we find the bite acts as an acid in the blood." Her main concern 
was the education of mountaineers and sheepherders, for whom spot- 
ted fever was an occupational hazard. Opining that sheepherders es- 
pecially needed her advice because of their "slothful nature," she stated: 
"In isolated places I have proposed the appHcation of freshly prepared 
mud, frequently changed, and much bathing if near streams. Also a 
free cathartic, with alkaline potions. Much fruit of a very acid nature 
and light diet with plenty of rest. The nightly removal of all clothing 
and the running of the hand over the body would warn us of the tick's 
presence in ample time for quick treatment and save many lives. "^"^ 

Occasionally, unorthodox remedies were bizarre. One married cou- 
ple who contracted the disease in Idaho attributed their recoveries to 
the ministrations of a Chinese doctor. The doctor, wrote the wife, 
"didn't come near the bed" but prescribed that they steep the teeth 
and toenails of a Chinaman in water to produce a curative brew. "I 
was to take V2 cup at 10 o'clock each day for 3 days," she stated, 
"and after 10 days or more I got up, but was never so weak in my 
life."^^ 

The exaltation of the common man with common sense contributed 
to another line of therapy in spotted fever. Representing one basic 



202 



Rocky Mountain Spotted Fever 



commonsense approach was Knute F. Turnquist, who suffered from 
the disease in Lo Lo, Montana, in 1906. Turnquist's self-designed 
treatment was direct and simple: he stayed drunk for two days. More 
often the commonsense approach was reflected in hope that an effective 
cure might lie in some familiar substance simply overlooked by the 
scientific community. And indeed, for a brief time in Montana, bicar- 
bonate of soda — ordinary baking soda— was thought to be the simple, 
surprise cure for spotted fever that no one had thought to investigate, 
because a number of patients recovered after being treated with it. 
During the devastating 19 21 tick season, however, when all eleven 
victims of spotted fever died, earlier hopes were dashed. A dejected 
Robert A. Cooley wrote in response to an inquiry about the treatment 
from a University of Nevada professor who had earlier visited Mon- 
tana: "At the time you were here the matter of bicarbonate of soda 
as a treatment for spotted fever was very much in our minds because 
of some recent experiences. It so happened that we had an unusual 
number of cases this year and this treatment was tried in a number 
of instances. The further experience we had was quite discouraging. 
The best we can say now is that there is a possibility that it may be 
of some value. "^^ 

Many people relied on folk remedies when they or their relatives 
fell ill with spotted fever. Far and away the most widely recommended 
was tea made from sagebrush. The use of sage tea, a woman from 
Washington State wrote to the RML, "is so simple you perhaps will 
think it a joke but I'm very sure it will work."^^ As proof of efficacy 
she cited the successful recovery of her sister and husband at different 
times. From Nebraska came a similar letter hailing the medicinal qual- 
ities of sage tea: "Have you found a cure for the Rocky Mountain 
spotted fever? If not will you try this tea: take the bark from the Idaho 
sage brush and make a medium strong tea. . . . The tea cured an uncle 
of mine in Idaho. "^^ So many letters suggesting the use of sage tea 
arrived at the laboratory, in fact, that Ralph R. Parker, whose duties 
included answering each letter, commented to a friend: "Of course, it 
has been laughed at, but actually I know of no attempt to determine 
if it does have value. Personally, I doubt it but my doubt is not backed 
by any evidence. I may get reckless some time and try it on a few 
guinea pigs. If spotted fever shouldn't kill them, perhaps the tea will."^^ 

Most advocates of sage tea pressed their cases on humanitarian 
grounds. "I just won't feel right keeping it to myself in case it would 
help some one," stated one correspondent.^^ Many other people, how- 
ever, sought compensation from the federal government for their as- 
sistance. Especially during the Great Depression, people seemed to feel 



spotted Fever Therapy 



203 



justified in asking for a portion of New Deal largess. In 1936, Thomas 
C. Cooper of Helena, Montana, offered to tell the laboratory a secret 
about the origins of wood ticks. "I just happen to stumble upon the 
original insect that turns into a wood tick last fall and this spring, I 
have positive proof that I am correct."^^ Having answered Cooper's 
letter in appropriately noncommittal but respectful language, Parker 
received a second missive requesting money. 

If I was financially situated so that it was possible, I would only be too glad 
to divulge this secret just for humaritarian [sic] sake, however, inasmuch as 
the government is spending money with its boondoggling ideas for much less 
important things than this, and also inasmuch as I am in my declining years 
now I see no reason why the government should not pay me for something 
that will benefit its citizens in health the most important of all things. . . . 
Awaiting further word from you.^^ 

Although Parker always explained that the government would not 
pay for information or treatments, he often offered to subject proposed 
therapies to analysis and testing at the RML. Many such offers were 
refused, but a number of preparations were indeed tested. In 1941, 
James Sproat, a physician in Portland, Oregon, sent one hundred 
ampules of a solution he claimed would cure spotted fever and a variety 
of other maladies. "Should the solution turn amber in color," stated 
his accompanying letter, "there is no cause for alarm as its efficacy is 
not effected [sic] in the least." Sproat commented that "the normal 
adult dose is 30 c.c. daily," injected intravenously, but he observed 
that a physician should exercise his own judgment about the efficacious 
dosage. "In treating chronic conditions, i.e., osteomyelitis and some 
forms of arthritis, over a long period of time, I have found the best 
dosage to be 30 c.c. every twenty-four hours. But in acute infections, 
i.e., carbuncles, infected wounds, erysipilis [sic] and similar acute in- 
fections, ... I have given ... as high as 4 or 5 doses of 30 c.c. each 
in twenty-four hours. "^^ Presumably the liquid failed to stand up under 
the laboratory's controlled tests, for nothing further was heard of it. 

Parker gathered two large files of folk, quack, freak, and mercenary 
letters relating to spotted fever therapy. It is significant, however, that 
the disease generated no major therapeutic scandal. Spotted fever's 
geographical isolation and relatively low incidence militated against 
widespread exploitation of victims. Furthermore, unlike chronic dis- 
eases in which the placebo effect often fooled patients into believing 
that quack therapies were efficacious, spotted fever ran a severe and 
unmitigated course from onset to recovery or to death. 

By the early 1930s nearly all investigators were disheartened about 
the prospects for discovering new chemical agents against infectious 



204 



Rocky Mountain Spotted Fever 



diseases. Not since the introduction of Paul Erhlich's Salvarsan had a 
chemical magic bullet been found that was effective against infectious 
diseases. One bright ray of hope broke into the dismal therapeutic 
situation during the late 1930s: the discovery of the powerful sulfon- 
amide drugs. In 1935, Gerhardt Domagk, director of research in 
experimental pathology and bacteriology at the research laboratories 
of the I. G. Farben Industrie in Elberfeld, Germany, announced that 
a red dye called Prontosil would cure mice of a lethal infection with 
hemolytic streptococci. The following year a British team got dramatic 
results with the drug in the treatment of streptococcal childbed fever. 
The active agent of the trademarked drug was soon found to be sul- 
fanilamide, and shortly afterward other sulfa derivatives were man- 
ufactured. The new sulfa drugs were hailed widely as wonder drugs, 
and even the editors of the generally restrained Science magazine 
echoed public optimism when they headlined a story on sulfas "Hope 
of Curing Tuberculosis, Influenza, and Leprosy."^^ 

At the National Institute of Health in Bethesda, Maryland, Norman 
H. Topping set about testing the effectiveness of Prontosil and sulfa- 
pyridine against spotted fever and endemic typhus. "Since chemo- 
therapy is being used so extensively in the treatment of a wide variety 
of infectious diseases, it was believed advisable to test in the laboratory 
the action of two of the most popular chemotherapeutic agents," he 
observed. His hopes, as well as those of people living in areas where 
spotted fever was prevalent, were dashed by the results of the exper- 
iments. Not only did the drugs have no positive effect on the course 
of either disease, but experimental animals treated with the sulfa drugs 
died sooner than control animals. "These experiments indicate," Top- 
ping wrote after his research, "that these two drugs should not be used 
in the treatment of typhus and Rocky Mountain spotted fever." As 
new varieties of the sulfa drugs were synthesized in the early 1940s, 
Ralph R. Parker and his colleagues at the RML tested them all— 
sulfathiazole, sodium sulfathiazole, sulfaguanidine, and sulfadiazine— 
with equally disappointing results. During this same period, Parker 
also tested two other drugs developed for wartime uses. Unfortunately, 
neither the antimalarial agent atabrine nor a promising antibiotic sub- 
stance tyrothricin protected guinea pigs from spotted fever. 

The results of such experiments, however, did not always affect the 
way practicing physicians treated their patients. Responding to the 
public's fascination with and insistence on taking medicine, some phy- 
sicians continued to administer sulfa drugs and other medications that 
had been demonstrated to be worthless in treating spotted fever. Top- 
ping himself noted this fact a few years later when he cooperated with 



spotted Fever Therapy 



205 



practicing physicians in conducting a clinical trial of an improved 
antiserum. "Several of the cases," he noted, had "received one of the 
sulfonamides; one case received intravenous metaphen; at least one 
case received large doses of quinine; several had intravenous fluids; 
several had blood transfusions; and one had intravenous immune hu- 
man serum. "^^ 

Because of the failure of know^n drugs to alter the course of Rocky 
Mountain spotted fever, the Spencer-Parker vaccine, introduced in the 
mid 1920s, provided the only efficacious medical strategy against the 
disease for more than tw^o decades. As dependence on the vaccine 
increased in infected areas, it became almost mythologically venerated. 
In 1937, Hollywood film makers seized upon this American success 
story and catapulted the tale of vaccine development into celluloid 
immortality. One of the genre of 1930s and 1940s medical triumph 
films, The Green Light W2is produced by Warner Brothers Studios and 
based loosely on a Lloyd C. Douglas novel in which scientists sought 
permission— a "green light"— to proceed with vaccine development. 
Starring Errol Flynn and Anita Louise, the film was spiced with a love 
triangle and a dramatic denouement when Flynn became a "human 
guinea pig" for the sake of science. Although the film apparently did 
well at the box office, reviews were mixed. One critic judged it a 
"pretty good picture," but another wished that it had been given a 
red light before production. 

In the Bitterroot Valley, where spotted fever was especially virulent, 
residents took extraordinary precautions in addition to their annual 
vaccinations with the Spencer-Parker vaccine. "Every spring the folks 
would shave the boys' hair so they could be sure no ticks were attached 
to us," recalled a native Bitterroot Valley resident, Nick Kramis, who 
lost an aunt to spotted fever and suffered a bout with it himself shortly 
after he began working in the tick-rearing room at the RML. Parents 
also issued stern warnings to their children against straying into in- 
fected areas. "We were strictly enjoined not to go on the west side of 
the Bitterroot River," stated Richard A. Ormsbee, another native Bit- 
terrooter. "My father enforced this with me, but I did not try to escape 
his interdiction, either! "^^ 

Throughout endemic areas across the country, spotted fever and its 
prevention became a regular spring public education feature in many 
newspapers.^^ By 1939, moreover, Nick Kramis, then the photographer 
at the RML, had produced a film entitled The Life History of the 
Rocky Mountain Wood Tick that enjoyed wide popularity among civic 
clubs and other groups who wished to educate their members about 
how to avoid the disease.^ ^ Lending support to this campaign, Parker 



2o6 



Rocky Mountain Spotted Fever 



occasionally published articles or provided information to science wri- 
ters. In 1933 he summarized much information in a Special Bulletin 
issued by the Montana State Board of Health. Infected people, he 
cautioned, should take no drugs without the advice of their physician. 
"Certain drugs, such as aspirin, which uninformed persons are likely 
to use, are deleterious in their effects and should be avoided."^^ Parker 
also noted that the Spencer-Parker vaccine was widely used as a treat- 
ment for spotted fever, "in spite of the fact that it is not recommended 
for this purpose. "^^ 

In 1944, just over a decade later, the American Medical Association's 
popular health journal Hygeia offered nearly the same advice. Its 
informational spotted fever article was adorned with a cartoon of a 
frantic mother calling her physician for information after finding a 
tick on one of her children. Having captured the reader's attention, 
the author hsted facts "parents should know about ticks and spotted 
fever to protect their children and spare themselves anxiety." The article 
provided detailed information about the epidemiology of spotted fever, 
how to remove and dispose of ticks properly, and how residents of a 
"woody section of a tick-infested area," could obtain the vaccine.^"^ 

Reviews of spotted fever written for medical audiences in the late 
1930s emphasized that the recommended treatment was "purely symp- 
tomatic and supportive." In such a paper written for the Rocky Moun- 
tain Medical Journal, George E. Baker admonished physicians against 
"an attitude of helplessness or hopeless inactivity." Carefully directed 
symptomatic care and supportive measures, he beHeved, aided patients 
in eliminating toxins from their bodies and in fighting against the 
invading organism. In addition. Baker recommended from his own 
experience— for it was not, he noted, mentioned in the literature— the 
administration of neosalvarsan dissolved in metaphen. The recoveries 
witnessed using these drugs, he speculated, might have been caused 
by "the bactericidal action of metaphen together with the spiroche- 
ticidal action of neosalvarsan upon a micro-organism which is bac- 
terium-like in character, but which has staining properties at least 
resembling that of spirochetes."^^ Plainly the same logic that motivated 
administration of Mercurochrome in the 1920s continued to inspire 
physicians in the early 1940s. 

Although chemotherapy appeared valueless against spotted fever, 
the development of Cox's yolk sac method to cultivate rickettsiae in 
large quantities rekindled interest in producing an antiserum against 
the disease. The medical crisis presented by World War II provided 
further impetus for research on this long-abandoned therapeutic strat- 
egy. In 1940, Norman H. Topping announced a hyperimmune rabbit 



spotted Fever Therapy 



207 




Norman H. Topping's research on spotted fever at the NIH was launched 
in 1938 when he fell ill with a laboratory-acquired infection. He recovered 
and made significant contributions to understanding the disease, including 
key epidemiological studies, work on the role of dogs as carriers of infected 
ticks, and development of an immune serum that lowered mortality 
considerably. (Courtesy of the National Library of Medicine.) 



serum against Rocky Mountain spotted fever that gave positive results 
in preliminary tests with guinea pigs and monkeys. Over the next 
three years, v^ith the cooperation of practicing physicians, he tested 
the new therapy on seventy-one unvaccinated, naturally infected pa- 
tients in both the eastern and western United States. From the begin- 
ning, results appeared promising. The antiserum reduced deaths from 
an expected rate of 18.8 percent to 3.8 percent.^^ 

In 1 94 1, Topping's antiserum received widespread publicity when 
it was used against the case of spotted fever suffered by J. Frederick 
Bell, a twenty-six-year-old student in bacteriology who visited the 
Rocky Mountain Laboratory in May to discuss cooperative work 
planned for the coming year. Because of a change in the timing of his 
visit, Bell was not inoculated before his arrival, as was customary. "As 
soon as I thought to ask him about spotted fever vaccination," Ralph 



208 



Rocky Mountain Spotted Fever 



R. Parker noted, "he received one injection."^^ Although Bell was not 
exposed to potentially dangerous areas of the laboratory, Parker was 
uneasy about the breach of routine requiring immunization of all 
visitors. Subsequent events underscored the reason for Parker's caution. 

On 1 6 May, Bell started east in the company of his brother-in-law 
Carl Larson, who later became director of the Rocky Mountain Lab- 
oratory. When they reached Rapid City, South Dakota, Bell entered 
the hospital with high fever, severe headache, general aching, and 
photophobia.^^ Since he had no rash, Q fever or typhus was originally 
suspected. "One day a beautiful young nurse came in and gave me a 
sponge bath," Bell recalled in a later interview. "After she left I looked 
down at my wrists and arms and there I could see the spots." He rang 
the bell to summon her back, whereupon he pronounced his own 
diagnosis: "I know what I've got at last— I've got Rocky Mountain 
spotted fever."^^ When the RML was informed of Bell's condition, 
Parker rushed 60 cc of Topping's experimental antiserum to the at- 
tending physician. Bell responded well, and newspapers in South Da- 
kota, Minnesota, and Iowa picked up the medical news, hailing the 
"New Serum" that rendered a "speedy cure" of Bell's illness. As a 
result, inquiries poured into the laboratory."^^ 

Because epidemic typhus was of such great concern in 194 1, a similar 
antiserum was soon prepared to combat it as well. During the 1943 
typhus epidemic in Egypt, described as one of the most severe that the 
country had experienced, this typhus antiserum was among the ther- 
apies studied by members of the U.S.A. Typhus Commission. Results 
of this test were similar to those in the spotted fever trials. Both 
spotted fever and typhus antisera were limited by the requirement that 
they be administered early in the course of a disease, preferably before 
the third day. Even so, they were the first therapeutic agents to make 
a clear difference in the prognosis of patients. 

While these studies were taking place, a new rickettsial menace, long 
known to the Japanese as tsutsugamushi but called scrub typhus by 
U.S. troops, threatened the Allied countermove to stem the Japanese 
advance in the Pacific. James J. Sapero and Fred A. Butler of the U.S. 
Navy described the situation early in 1942, when U.S. forces began 
to occupy "numerous widely separated tropical islands throughout a 
vast subequatorial region." Although the area was known to be a 
hyperendemic focus of disease, most medical officers were unfamiHar 
with scrub typhus and other exotic tropical maladies such as malaria, 
dengue, dysentery, yaws, filariasis, and leprosy. "There followed, as a 
consequence," observed Sapero and Butler, "a series of outbreaks of 
tropical diseases in epidemic proportions of a magnitude and potential 



spotted Fever Therapy 



209 



threat seldom if ever exceeded in American military history.'"^^ 

Scrub typhus, one of the most serious of these diseases, disabled 
some 18,000 Allied troops, including 6,685 U.S. servicemen between 
January 1943 and August 1945. Fatality rates varied from a lov^ of 
0.6 percent in some regions to as high as 35 percent in others; there 
were 234 deaths among U.S. troops. "^"^ Japanese miHtary forces suffered 
less from tsutsugamushi, doubtless because the endemic disease v^as 
familiar to Japanese physicians and pubUc health workers. Except for 
the 1908 comparative study between Rocky Mountain spotted fever 
and tsutsugamushi made by U.S. Army physicians Percy M. Ashburn 
and Charles F. Craig, few western studies on the disease had been 
pursued. In contrast, Japanese investigators had continued to study 
the two diseases into the 1930s, even though two of them died from 
laboratory-acquired spotted fever infections during their research. The 
two Japanese who succumbed were Kokyo Sugata, an assistant of 
Norio Ogata of the Chiba Medical College, who died on 4 July 193 1; 
and Masajiro Nishibe, a professor at the Niigata Medical College, 
who died on 13 August 1932."^^ 

Usually scrub typhus was diagnosed by clinical observation of typical 
typhus-like symptoms: high fever, headache, muscle and joint pain, 
and a rash. For laboratory confirmation, a Weil-Felix test had been 
developed during the 1920s and 1930s by British researchers and their 
colleagues at the Institute of Medical Research in Kuala Lumpur, 
Federated Malay States. They had observed that the sera of tsutsu- 
gamushi patients reacted positively to the OX-K strain of B. proteus 
and negatively to the OX- 19 strain."^^ 

The U.S.A. Typhus Commission began to study scrub typhus, noted 
its director, Stanhope Bayne-Jones, "because of its last name. . . . When 
we took in scrub typhus, no one stopped to ask whether the Executive 
Order apphed or not." Because it caused so many disabihties and 
deaths among Allied troops, the Typhus Commission brought in a 
variety of experts to attack this capricious malady, which often struck 
one group of soldiers while leaving others nearby untouched. Cornelius 
B. Philip and Glen Kohls, entomologists who had left the RML to join 
the military after war broke out, sought to identify arthropod vectors 
of the disease, which had been suspected because victims exhibited an 
eschar, or initial lesion, a characteristic of the more famiHar European 
tick-borne disease, boutonneuse fever. Francis G. Blake, dean of the 
Yale University School of Medicine, and Kenneth F. Maxcy, professor 
of epidemiology at Johns Hopkins School of Hygiene and Public 
Health, investigated the epidemiology and medical treatment of the 
disease."^^ 



2IO 



Rocky Mountain Spotted Fever 



By the end of the war, two major Hnes of defense against scrub 
typhus had been developed. First, the U.S. Army launched preventive 
education efforts, including posters describing the mite, where it was 
likely to be found, and how soldiers should prepare their campsites 
to avoid it. Second, investigators funded by the Medical Research 
Committee of the Office of Scientific Research and Development de- 
veloped chemicals to impregnate clothing that would repel the tsut- 
sugamushi mite. Dimethyl phthalate was initially chosen, but in 1945 
the War Department replaced it with benzyl benzoate, because it would 
withstand more launderings before having to be reapplied. Even so, 
soldiers' clothing had to be retreated every two weeks. 

Military physicians who cared for scrub typhus victims adopted 
supportive therapy like that used for years against Rocky Mountain 
spotted fever. Norman H. Topping believed that an antiserum should 
be effective for treatment and perhaps even for prophylaxis of scrub 
typhus. With the eschar as an early diagnostic feature, Topping rea- 
soned, antiserum could be given earher and with greater benefit. By 
1945 he had prepared one that gave promising results in mice. Research 
by the U.S. Army, U.S. Navy, and U.S. Public Health Service also 
focused on the development of a vaccine against the disease. Before 
either vaccine or antiserum could be tested, however, the war ended."^^ 

A similar situation occurred in the Mediterranean theater with yet 
another rickettsial disease. During the winter of 1944 and spring of 
1945, Alhed troops in this region fell ill with a malady first termed 
the Balkan grippe but soon shown to be Q fever. The sudden ap- 
pearance of this disease in the Mediterranean area foreshadowed later 
findings that it was widespread around the globe, rather than confined 
to Australia and to the western United States, as had been believed 
when it was first discovered. 

Experience with all the rickettsial diseases during World War II led 
to a much more specific understanding of their pathologic mechanisms. 
In contrast to earlier observations, which were generally limited to 
descriptions of damage to particular tissues, wartime physiological 
research illuminated the dynamic biological mechanisms involved. In 
1944, Theodore E. Woodward and Edward F. Bland, members of the 
U.S.A. Typhus Commission, reported that studies of typhus in French 
Morocco had revealed the "overwhelming generalized involvement" 
of the peripheral circulatory system. Rickettsiae invaded the entire 
circulatory tree, causing swelling of the endothehal cells. By occluding 
blood flow, they gave rise to the formation of clots in the smaller and 
occasionally even the larger blood vessels. This damage produced "an 
increase of capillary permeability," which altered the electrolytic com- 



spotted Fever Therapy 



211 



position of the blood and lowered the osmotic pressure as plasma 
proteins escaped into the tissues. These phenomena further starved the 
capillaries of needed oxygen and nutrients, thus setting up a vicious 
cycle that culminated in circulatory failure/^ 

To combat this v^idespread damage, aggressive supportive therapy 
was indicated. The same year that Woodward and Bland published 
their prescription for typhus therapy, a North Carolina physician, 
George T. Harrell, and his colleagues outlined a similar program for 
the treatment of Rocky Mountain spotted fever. Unlike the undiffer- 
entiated "good nursing" recommendations of earlier decades, the sup- 
portive therapies advocated by both groups were highly specific: ad- 
equate fluid intake, blood plasma transfusions if necessary, ammonium 
or sodium salts to improve hypochloremia, a nourishing protein and 
carbohydrate diet, and abandonment of the common practice of ad- 
ministering digitalis to stimulate the heart except to treat critical heart 
problems. 

Such a program was unfortunately necessary because the most stun- 
ning medical triumph of the war years — the development of penicillin — 
had proved valueless against the rickettsial diseases. Discovered in 
1928 by Alexander Fleming, the mold Penicillium notatum had been 
largely ignored until an expensive cooperative effort between phar- 
maceutical firms and the U.S. government made large-scale production 
possible. By 1943 tests in several civiHan hospitals had demonstrated 
penicillin's potency against a host of infections. Not a chemical com- 
pound like the sulfa drugs, this antibiotic was a substance produced 
by living organisms that was antagonistic to the growth of many 
bacteria. Here, at last, was the long-sought "magic bullet" that cured 
staphylococcal infections, pneumococcal pneumonia, rheumatic fever, 
syphilis, and gonorrhea. 

Tests of the effectiveness of penicillin against Rocky Mountain spot- 
ted fever and other rickettsial diseases were conducted in 1945 at the 
Rocky Mountain Laboratory and in the research laboratories of the 
Sharp and Dohme pharmaceutical house. At Sharp and Dohme, Flor- 
ence K. Fitzpatrick treated spotted-fever-infected guinea pigs within 
forty-eight hours after the onset of fever. All the animals died. Blood 
plasma levels of the drug, she noted, were sufficient to expect recovery 
had penicillin been of any value. 

Even though penicillin had proved to be of no use against rickettsial 
diseases, its example spurred further research for a chemical or anti- 
biotic agent that would supplant the limited value of antisera. Early 
efforts followed a lead suggested in 1937 by Hans Zinsser and E. B. 
Schoenbach at Harvard Medical School. They had demonstrated that 



212 



Rocky Mountain Spotted Fever 



the rate of intracellular multiplication of rickettsiae in tissue cultures 
was determined by the metabolic rate of the host cells. Under conditions 
of high metabolic activity, Httle or no multiplication of the intracellular 
parasites took place. Only under conditions of reduced metaboUc ac- 
tivity was active multiplication noted.^^ This information set investi- 
gators searching for a nontoxic substance that would increase cellular 
metabohsm and thereby inhibit rickettsial multiplication. 

In 1942 para-aminobenzoic acid, commonly called PABA and gen- 
erally considered to be a vitamin, was identified as a promising an- 
tirickettsial agent. In a classified report to the Division of Medical 
Sciences of the National Research Council, John C. Snyder, John Maier, 
and C. R. Anderson described its effectiveness in reducing mortaHty 
from experimental murine typhus in white mice.^^ A year later, H. L. 
Hamilton, Harry Plotz, and Joseph E. Smadel reported to the director 
of the U.S.A. Typhus Commission on PABA's effect on the growth of 
typhus rickettsiae in the yolk sac of the infected chick embryo. 

The first large-scale test of PABA was conducted in 1943, a part of 
the therapeutic trials made during the typhus epidemic in Egypt. The 
results indicated that PABA ameliorated the clinical course of the dis- 
ease if it was started during the first week of illness. The drug produced 
no unfavorable effects with the exception of a tendency to develop a 
low white blood cell count, which could be monitored. When Andrew 
Yeomans and his colleagues published these findings in the Journal of 
the American Medical Association, its editors wondered, "What effect 
will para-aminobenzoic acid and related compounds have on Rocky 
Mountain spotted fever and other rickettsial diseases?" That question 
was soon answered. In 1945, Ludwik Anigstein and Madero N. Bader 
reported that PABA was indeed efficacious against spotted fever in 
guinea pigs. Shortly thereafter, Harry M. Rose and his colleagues at 
Columbia University College of Physicians and Surgeons reported the 
first clinical results of a single human case of Rocky Mountain spotted 
fever treated with PABA. The patient, a woman, improved rapidly after 
twenty-four hours of therapy.^^ 

Additional evidence for the efficacy of PABA therapy was soon 
amassed. The cases of spotted fever suffered by a Fairfax, Virginia, 
couple were cured with PABA after they failed to respond to immune 
rabbit serum therapy. A group of cases studied by physicians in Wil- 
mington, Delaware, indicated that spotted fever responded even more 
sensitively to PABA than did typhus. They also, however, noted the 
limitations of the drug as reflected in its failure to cure a sixty-seven- 
year-old man with long-standing renal disease and a history of heart 
attack. This case, they stated, "may serve to illustrate the point . . . 



spotted Fever Therapy 



213 



that p-aminobenzoic acid retards or prevents the spread and prolif- 
eration of the rickettsias in the body but is not an antidote for any 
toxin already released and does not repair damage already done."^^ 

PABA was rickettsiostatic, not rickettsiocidal— that is, it inhibited 
further growth of rickettsiae but did not kill them outright. Because 
of this, it was essential that treatment begin as soon as possible. Once 
the organisms had damaged the tissues and multiplied to large numbers, 
the drug could not stop them. The giant step in therapy represented 
by PABA, however, inspired greater confidence than ever before among 
physicians. A review of spotted fever written in 1947 by Samuel F. 
Ravenel reflected this greater sense of knowledge about and control 
over the disease gained during the war years. "In the early days, the 
treatment of this disease was symptomatic, which simply enabled the 
patient to die or recover somewhat more comfortably." In contrast, 
Ravenel was able to outline a comprehensive treatment plan that should 
enable any physician to do battle with confidence against Rocky Moun- 
tain spotted fever. ^° 

Although PABA therapy enriched the physician's armamentarium in 
the fight against spotted fever, it was soon eclipsed by more powerful 
drugs. Unlike the development of the Spencer-Parker or Cox vaccines, 
a cure for spotted fever did not emerge from a direct attack on the 
disease in isolation. Rather, it resulted from planned, persistent, and 
expensive empirical searches for antibiotics undertaken by pharma- 
ceutical companies. The example of penicillin research, with its large 
investment and larger profits, was the stimulus for the effort to find 
antibiotics against other diseases. Not yet knowing the structure, much 
less the physiology, of rickettsiae or viruses, investigators proceeded 
without benefit of detailed knowledge about the organisms they were 
combating. 

Even so, by the late 1940s, Harry F. Dowling noted in his compre- 
hensive study of infectious disease therapy, Fighting Infection^ "at least 
half a dozen companies had teams of investigators actively looking 
for antibiotics."^^ One of them, Parke, Davis and Company, estabfished 
a research grant at Yale University to enable Paul Burkholder, a bot- 
anist, to search soil samples for microorganisms with antibiotic po- 
tentialities. He isolated a promising mold from Venezuelan soil, which 
was subsequently named Streptomyces Venezuela. Parke, Davis scien- 
tists extracted a substance from it that inhibited the growth of a number 
of pathogenic bacteria. The new antibiotic was named chloramphenicol 
and given the trade name Chloromycetin.^^ 

In their publication announcing the discovery of the drug, Parke, 
Davis scientists noted that Chloromycetin was more effective than 



214 



Rocky Mountain Spotted Fever 




With the discovery of broad-spectrum antibiotics, Rocky Mountain spotted 
fever became a curable disease. Aureomycin and Terramycin were trade 
names for the tetracycline drugs. Chloramphenicol was sold under the 
name Chloromycetin. Potentially toxic side effects of the drugs were not 
recognized for nearly a decade after they were introduced. (Courtesy of the 
Rocky Mountain Laboratories, NIAID.) 



PABA against Rickettsia prowazekii, the organism that caused epidemic 
typhus, in experiments on chicken embryos and mice.^^ They sent 
samples of the promising drug to Joseph E. Smadel, then scientific 
director of the Walter Reed Army Institute of Research, who had a 
"working arrangement" with Parke, Davis to test "any new anti- 
microbial drugs which exerted even the slightest inhibitory effect for 
viral and rickettsial agents. "^"^ WTien he got similar results in his lab- 
oratory, Smadel enthusiastically recommended immediate trials in hu- 
mans. 

Shortly thereafter, Eugene H. Payne of Parke, Davis took a team of 
scientists to Bolivia, where an epidemic of typhus was raging. The 
power of this new drug against typhus was dramatically confirmed. 
An anecdote recounted by Dowling bears repeating here as an illus- 



spotted Fever Therapy 



215 



tration: "In collaboration with local doctors, . . . [Payne] treated 22 
of the sickest patients, five of whom had been listed as certain to die. 
All recovered, including one for whom the death certificate had already 
been filled out and signed, awaiting only the insertion of the hour of 
death." Smadel's tests of Chloromycetin on typhus patients in Mexico 
were equally successful. He then arranged with Raymond Lewthwaite, 
director of the Institute for Medical Research at Kuala Lumpur, Ma- 
laya, to conduct field trials of the new antibiotic on scrub typhus cases. 
All ninety-four patients treated with it recovered. 

On the basis of these spectacular results, Maurice C. Pincoffs and 
his colleagues of the University of Maryland School of Medicine in 
Baltimore cooperated with Joseph E. Smadel of the Army Medical 
School to test Chloromycetin furnished by Parke, Davis against spotted 
fever. Patients were given tablets of the drug in dosages based on body 
weight that had proved effective against scrub typhus— an initial large 
dose followed by smaller doses every three hours. No toxicity was 
observed, but the researchers noted that the drug had not been used 
over a long period of time. The results of the therapy were indisputably 
positive. Irrespective of the height of the preceding fever or the age of 
the patient, body temperature fell to normal within seventy-six hours 
after the initial dose. The average duration of fever was a mere 2.2 
days. Shortly thereafter, other researchers confirmed these results and 
the popular press acclaimed Chloromycetin as the "greatest drug since 
penicillin."^^ 

Almost simultaneously with the development of chloramphenicol, 
researchers at Lederle Laboratories announced the development of an 
antibiotic from Streptomyces aureofaciens, which, because of its gold 
color, was named Aureomycin. In June 1948 a research group at 
Children's Hospital in Washington, D.C., collaborated with members 
of the Department of Preventive Medicine at Johns Hopkins University 
School of Medicine to test Aureomycin in thirteen patients suffering 
from Rocky Mountain spotted fever. "The response of these patients 
has been impressive," the researchers wrote, "and it is apparent that 
Aureomycin is an effective therapeutic agent."^^ Shortly thereafter, 
researchers at a third pharmaceutical house, Charles Pfizer and Com- 
pany, produced another antibiotic effective against rickettsial diseases. 
Isolated from Streptomyces rimosus, this drug was called Terramycin. 
When the chemical structures of Aureomycin and Terramycin were 
elucidated, they were found to be nearly identical. Together they be- 
came known as the tetracyclines, and, with later analogues and with 
chloramphenicol, they were termed broad-spectrum antibiotics. These 
drugs were effective not only against rickettsial infections and those 



zi6 



Rocky Mountain Spotted Fever 



diseases that had yielded already to peniciUin but also against diseases 
whose stubborn bacterial agents had resisted all earlier therapies, in- 
cluding typhoid fever, brucellosis, mycoplasma pneumonias, and chla- 
mydial infections. 

The advent of antibiotics effective against rickettsial diseases 
crow^ned the av^^esome achievements of scientific and medical research 
during the 1940s. Through research on the atomic bomb, physicists 
had opened a qualitatively new field that held great promise in medicine 
and in world energy production while simultaneously threatening 
worldwide destruction. Atomic power and antibiotics symbolized the 
power of research that had also produced a host of less-publicized 
discoveries, from improved blood transfusion techniques to radar. 
These achievements led many leaders of the scientific and medical 
communities to argue forcefully for expanded federal funding of re- 
search, especially in basic studies that formed a broad body of knowl- 
edge from which specific applications might emerge. This effort, 
according to Charles V. Kidd, was "the loudest, most expensive, most 
persistent, most calculating, most emotional, most effective and socially 
useful propaganda campaign" ever mounted on behalf of science. 

Of many proposals, none was more far-reaching than that prom- 
ulgated by the Committee on Science and Society of the American 
Association for the Advancement of Science. Twelve points for a na- 
tional research policy emerged from a symposium held in December 
1944. Point 2 called for "extending systematic research into every field 
or activity of life, as a considered policy of critically examining what- 
ever we beheve and do, and proceeding to a revision of established 
assumptions and practices wherever research reveals they are required 
or desirable." Point 9 went so far as to assert that research should be 
a coordinate function of the U. S. government equal to the legislative, 
executive, and judiciary.^^ ' 

During the next decade. Congress and both Democratic and Re- 
publican presidents supported the expansion of federally sponsored 
scientific and medical research— even if they declined to grant science 
coequal status under the Constitution. The National Science Foun- 
dation was created, and the NIH flourished with the estabfishment of 
a program of grants to university researchers and the creation of several 
new institutes. Discussions about basic and applied research, more- 
over, produced a new agenda for research at the NIH. Its traditional 
public health responsibihty of assisting states with on-site disease prob- 
lems, such as the Rocky Mountain spotted fever work in Montana, 
was transferred to the newly created Communicable Disease Center, 
later called the Centers for Disease Control, in Atlanta, Georgia. An 



spotted Fever Therapy 



217 



enlarged and reorganized NIH claimed basic studies as its mission, 
utilizing a document on postwar science policy widely known as the 
Steelman Report to articulate the distinctions between basic and ap- 
plied research/^ Laboratory studies to uncover new information were 
generally regarded as basic research. Gathering statistics on the inci- 
dence of disease fairly clearly fell in the applied category. These dis- 
tinctions, of course, were somewhat subject to interpretation. Much 
epidemiological research and field studies of vector-borne diseases were 
often difficult to classify. 

The NIH director, Rolla E. Dyer, set about applying the terms of 
the new mandate to the programs of the several institutes that com- 
prised the now plural National Institutes of Health. Among these was 
the National Microbiological Institute, comprised of the agency's his- 
toric research programs in infectious and tropical diseases and its work 
in biologies standards. Although the Rocky Mountain Laboratory 
was made a coequal branch of the new institute, the focus on basic 
research presented a somewhat awkward problem for RML, which 
had served during the war years principally as a vaccine factory— 
clearly an applied rather than a basic function. Furthermore, applied 
research was conducted by its staff of entomologists, who enjoyed a 
worldwide reputation as authorities on tick taxonomy, and by its 
serologists, who performed laboratory tests for physicians and public 
health agencies throughout the northwestern states. These duties, how- 
ever, overlapped with other, more basic studies, such as identifying 
tick vectors of diseases and studying the antigenic relationships among 
disease organisms. As discussions about the laboratory's postwar re- 
search program continued, NIH administrators moved rapidly to trans- 
fer production of yellow fever and rickettsial vaccines to the private 
sector. The last batches of Spencer-Parker vaccine made from tick 
tissues were produced in 1948. The chief vaccine maker, Earl Malone, 
who had supervised production since the mid 1920s, turned to other 
assignments until his retirement in 1958.^^ 

In January 1949 Victor H. Haas, first director of the National Mi- 
crobiological Institute, traveled to Montana to discuss with Ralph R. 
Parker how RML should redirect its research in light of the new NIH 
emphasis. The ambiguity of the Steelman distinctions between basic 
and applied research was clearly revealed in the interchanges between 
Haas and Parker at the conference. "It is especially important," Haas 
stated to Parker, 

that we shall conform to the policy decisions made by higher levels that the 
function of the N.I.H. is basic research. ... I think many things that were 



2l8 



Rocky Mountain Spotted Fever 



fundamental research a year ago or a month ago or lo years ago are not 
fundamental research today. Let us say, for example, that when the natural 
history of spotted fever was unknown, investigation of that problem was 
fundamental research, just as I think the investigation of equine encephalo- 
myelitis is fundamental research today. 

Parker took issue: "I would disagree that we know the natural history 
of spotted fever— we know very little about it." Haas replied, "That 
is right. I only used that as an illustration."^^ 

Although Parker was prepared to redirect the RML's research in 
accordance with NIH policy, he was never able to implement the new 
plans. On 4 September 1949 he suffered a heart attack and died.^^ In 
the history of Rocky Mountain spotted fever, Parker's death may be 
viewed as a watershed. He had investigated the ecology of spotted 
fever, participated in the development of the tick tissue vaccine, su- 
pervised the production of the Cox vaccine, personally tested the ef- 
ficacy of numerous drugs, and witnessed the introduction of effective 
broad-spectrum antibiotics. Parker probably possessed a broader 
knowledge of spotted fever than did any other single person. After his 
death the history of spotted fever became less directly tied to western 
Montana and to the Rocky Mountain Laboratory, although that fa- 
cility continued to serve as a major center for rickettsial research. 

In the late 1940s the wartime vocabulary of conquest, triumph, and 
victory seemed particularly appropriate to describe the half-century 
struggle to prevent and cure the most severe rickettsial disease in the 
western hemisphere. And indeed, in 1949 the first of a genre of "con- 
quest" articles appeared. It was the first Howard Taylor Ricketts Award 
Lecture at the University of Chicago. The speaker was Russell M. 
Wilder, then on the staff of the Mayo Clinic, who had assisted Ricketts 
in the 19 10 research on typhus fever that took his Hfe. Entitling his 
lecture "The Rickettsial Diseases: Discovery and Conquest," Wilder 
proclaimed, "This discovery of a cure . . . represents the final chapter 
of an epic."^° His choice of the word final may have been premature, 
but without doubt the impact of antibiotics was of epic proportion. 
By fulfilling the promise of medical research, these "miracle drugs" 
justified the persistent faith and optimism of investigators and laymen 
alike. 



Chapter Eleven 



Spotted Fever 
after Antibiotics 



Experience has shown that success may be temporary when all the answers 
are not known. 

Mack I. Shanholtz, Virginia State Health Commissioner, 1961 



During the 1950s, Rocky Mountain spotted fever seemed nearly to 
disappear in the United States. The number of reported cases fell from 
570 in 1949 to 301 in 1953. Throughout the remainder of the decade, 
the incidence of the disease hovered at 250—300 cases with fewer than 
two dozen deaths per year/ Except for the families and friends of the 
victims, most people could argue with conviction that antibiotics and 
insecticides had eHminated spotted fever as a threat to modern society. 
Because Rickettsia rickettsii had not been eradicated, however, the 
history of Rocky Mountain spotted fever did not end with antibiotics. 
The period between the late 1940s and the early 1970s may be char- 
acterized as a time of little drama in the story, yet it was during these 
years that much of the morphology, ecology, and physiology of 
R. rickettsii was elucidated. 

One significant portion of the ecology of spotted fever was defined 
between 1935 and 1950. During this period the disease was shown 
to be widespread throughout— and apparently exclusive to— the west- 
ern hemisphere.^ In South America by the early 1940s spotted fever 
was known to exist in Tobia, Colombia, and in rural areas of Sao 
Paulo, Minas Gerais, and Rio de Janeiro, Brazil.^ In 1938 the first 
figures on spotted fever in Canada revealed that, although the disease 
had been known since 1923, only eight cases were officially docu- 
mented."^ During the next decade, a project to amass data on spotted 
fever and bubonic plague in Canada revealed that cases of spotted 
fever were known in British Columbia, Alberta, and Saskatchewan, 
with most cases occurring in southeastern Alberta. Three species of 
spotted fever tick vectors were identified, but only D. andersoni, abun- 



219 



220 



Rocky Mountain Spotted Fever 



150 -| 



i«0 - 




q4 ^ ; ^ , , 4-0 

1940 I9';5 1950 1955 i960 1965 1970 



Deaths and ratios of cases to fatalities of Rocky Mountain spotted fever in 
the United States, 1940-70. The solid line represents the number of deaths; 
the dotted line tracks the ratio of cases to fatalities— that is, the mortality 
percentage. The data for 1968 were provisional. The impact of broad 
spectrum antibiotics, introduced in 1948, is dramatically apparent. 
(Reproduced from Michael A. W. Hattwick, "Rocky Mountain Spotted 
Fever in the U.S., 1920-1970," Journal of Infectious Diseases 124 [1971]: 
112-14.) 

dant in the southern part of the three western provinces, was known 
to harbor virulent strains of R. rickettsii. The small number of infected 
ticks in nature and the tedious work of surveying them were under- 
scored by the Canadian report: only 5 of 72,227 ticks collected in 
British Columbia and only 10 of 49,201 collected in Alberta were 
demonstrated to be infective.^ 

For some time, spotted fever seemed curiously absent from Mexico 
and other Central American countries. Writing in 1943, Gordon E. 
Davis of the Rocky Mountain Laboratory observed that it hardly 
seemed "credible that a disease present in southwestern Canada, 



spotted Fever after Antibiotics 



221 



throughout the United States, in Colombia, and Brazil should be en- 
tirely absent" from the Central American region.^ Indeed, the following 
year "an acute petechial fever with a high death rate," was reported 
from the districts of Choix and Fuerte de Sinaloa in Mexico. Local 
residents, who called the affliction fiebre de Choix or fiebre manchada^ 
reported to Miguel E. Bustamante and Gerardo Varela of the Instituto 
de Salubridad y Enfermedades Tropicales in Mexico City that the 
affliction appeared each year. A 75 percent mortality, typical rickettsial 
symptoms, and the presence of ticks strongly suggested Rocky Moun- 
tain spotted fever.^ Subsequent studies confirmed that spotted fever 
existed alongside murine typhus in the Mexican states of Durango and 
Sinaloa, and that it occurred with epidemic typhus in San Luis Potosi 
and Veracruz. All three rickettsial diseases occurred in Coahuila. Only 
in Sonora did spotted fever exist in isolation. Arthropod vectors found 
naturally infected were R. sanguineus in the north and northeast 
regions and A. cajennense on the east Mexican coast.^ 

In 1950 spotted fever was first reported in Panama. Although the 
diagnosis of the first Panamanian case was made upon autopsy, the 
next two reported victims were treated with antibiotics and recovered. 
Carlos Calero and Jose M. Nuiiez of the Panama Hospital and Santo 
Thomas Hospital in Panama and Roberto Silva-Goytia of the Instituto 
de Salubridad y Enfermedades Tropicales in Mexico City found that 
infections occurred in both rural and urban settings across the isthmus. 
By 1953, Enid C. de Rodaniche at Gorgas Memorial Hospital had 
recovered Rickettsia rickettsii from naturally infected Amblyomma 
cajennense ticks, already known as a vector of spotted fever in Co- 
lombia, Mexico, and Brazil. Because this tick was abundant and at- 
tacked humans "readily" in all stages, Rodaniche wondered why clin- 
ical spotted fever had not been encountered across the isthmus with 
greater frequency in the past.^ 

Since spotted fever had been identified in North, South, and Central 
America, Mexican investigators Bustamante and Varela proposed that 
its name be changed to American spotted fever to eliminate its mis- 
leading exclusive association with the Rocky Mountain area of North 
America. A BraziHan investigator argued that all geographical adjec- 
tives should be abandoned and the disease called simply spotted fever. 
U.S. investigators W. M. Kelsey and G. T. Harrell suggested that tick- 
borne typhus was the most appropriate scientific designation. None 
of these proposals, however, gained widespread support. The popular 
name Rocky Mountain spotted fever simply could not be dislodged. 

Complacency about spotted fever, of course, was abetted by a pleth- 
ora of popular articles that emphasized the miraculous properties of 



222 



Rocky Mountain Spotted Fever 



antibiotics and insecticides in controlling infectious diseases. A fed- 
erally funded flea control project begun in 1945 demonstrated beyond 
cavil DDT's power against the vectors of murine typhus. In nine south- 
eastern states and in Texas— where 92 percent of all cases of murine 
typhus occurred— DDT dusting produced a 62 percent decline in cases. 
"Barrier spraying" against ticks along roadsides, the dusting of dogs 
with DDT, and the development of more effective tick repellents played 
a similar role in the containment of spotted fever. Confidence in the 
efficacy of insecticides ran so high, in fact, that some scientists joked 
that these chemicals might render their positions obsolete. 

Control of rickettsial diseases with chemical pesticides, however, 
lasted for less than two decades. By the 1960s irrefutable evidence had 
been amassed that mosquitoes, lice, mites, and other arthropod vectors 
could develop resistance to insecticides. In Silent Spring, her celebrated 
book on the dangers of the indiscriminate use of such chemicals, Rachel 
Carson recorded the declining power of DDT against typhus after its 
initial success during World War II. 

The control of body lice in Naples was one of the earliest and most publicized 
achievements of DDT. During the next few years its success in Italy was 
matched by the successful control of lice affecting some two million people 
in Japan and Korea in the winter of 1945-46. Some premonition of trouble 
ahead might have been gained by the failure to control a typhus epidemic in 
Spain in 1948. Despite this failure in actual practice, encouraging laboratory 
experiments led entomologists to believe lice were unlikely to develop resist- 
ance. Events in Korea in the winter of 1950-51 were therefore startling. When 
DDT powder was applied to a group of Korean soldiers the extraordinary 
result was an actual increase in the infestation of lice. When lice were collected 
and tested, it was found that 5 per cent DDT powder caused no increase in 
their natural mortality. Similar results among lice collected from vagrants in 
Tokyo, from an asylum in Itabashi, and from refugee camps in Syria, Jordan, 
and eastern Egypt, confirmed the ineffectiveness of DDT for the control of 
lice and typhus. When by 1957 the list of countries in which lice had become 
resistant to DDT was extended to include Iran, Turkey, Ethiopia, West Africa, 
South Africa, Peru, Chile, France, Yugoslavia, Afghanistan, Uganda, Mexico, 
and Tanganyika, the initial triumph in Italy seemed dim indeed. 

As with insecticides, broad-spectrum antibiotics were used widely, 
even indiscriminately, during the 1950s. Among those investigators 
who monitored the incidence of spotted fever during this decade, it 
was apparent that the popular drugs masked its true incidence in the 
United States. "It is probably safe to say," wrote the authors of a 1955 
review paper, "that a relatively small percentage of Rocky Mountain 
spotted fever and typhus infections now develop to the point of com- 
plete diagnosis and reporting." Further complicating the picture was 
the influence of antibiotics on diagnostic tests. Studies at the Rocky 



spotted Fever after Antibiotics 



223 



Mountain Laboratory revealed that the appearance of antibodies in 
both the Weil-FeHx and the complement fixation tests was altered if 
the patient had received antibiotics. It also became increasingly hard 
to obtain blood samples that show^ed a change in antibody level. Pa- 
tients receiving antibiotics rarely returned to their physicians for a 
follow-up blood test. It thus became virtually impossible to confirm 
suspected cases. 

The popularity of the "miracle drugs," moreover, deflected early 
reports about their toxic side effects. Chloramphenicol, which had 
passed toxicity tests in animals and appeared to have no adverse effects 
other than causing temporary anemia, was in wide use before its 
dangers came to pubhc attention. Evidence gathered as early as 1950 
that the drug could cause a dangerous depression of the blood marrow 
resulting in fatal aplastic anemia at first attracted little attention. Be- 
cause death often occurred two or more months after treatment had 
stopped, it was often difficult to relate it to the earher administration 
of chloramphenicol. In 1952, however, accounts of an entire series of 
such cases temporarily restricted the use of the drug. Soothing phar- 
maceutical propaganda, however, soon restored the use of chloram- 
phenicol to a high level. Further evidence of the drug's hazards ap- 
peared some years later, when it was often administered to newborn 
babies prophylactically. Many of these infants developed the so-called 
grey syndrome, named for the ashen grey pallor that accompanied 
circulatory collapse and death. It was not until 1959, however, that 
a therapeutic experiment at the Los Angeles County Hospital dem- 
onstrated chloramphenicol's causative connection to this condition. 

By the early 1960s medical texts began recommending against the 
use of chloramphenicol for rickettsial infections, usually noting the 
tetracyclines as effective alternatives. Even as these texts came off the 
presses, additional reports appeared, suggesting that the tetracyclines 
might also be hazardous, especially to patients' teeth. Since 1957 the 
tetracyclines had been known to have an affinity for bone tissue. 
Because the drugs fluoresced under ultraviolet light, scientists could 
identify the sites in the body where they lodged after treatment. In 
1962, I. S. Walton and H. B. Hilton at the King Edw^ard Memorial 
Hospital for Women in Perth, Australia, published the results of a 
study on fifty babies who had received the drugs during their first few 
weeks of life. Forty-six of the children suffered stains on their primary 
teeth. As with those children treated with chloramphenicol, nearly half 
of these babies had been given tetracyclines prophylactically rather 
than for any medical problem. In 1963 investigators at the National 
Institute of Dental Research pubUshed a review article alerting the 



224 



Rocky Mountain Spotted Fever 



medical community to the dangers of these drugs. "TetracycHne is the 
drug of choice in many infections in which the consequences of the 
infection outweigh the possible damage to the teeth," they concluded, 
but they warned about the hazards of injudicious use.^^ 

With a death rate of over 20 percent in untreated persons. Rocky 
Mountain spotted fever was one of those diseases in which the risks 
of the tetracyclines or even chloramphenicol seemed worth taking. 
When the 1950s enthusiasm for antibiotics gave way by the 1970s to 
extreme caution in prescribing such drugs, those physicians who fre- 
quently treated spotted fever cases had no hesitation about their use. 
Thus a 1977 paper in the Journal of the American Medical Association 
suggesting that the tetracyclines should be virtually abandoned drew 
sharp criticism from southeastern physicians located in endemic spot- 
ted fever areas. Noting that a single, short course of oxytetracycline 
or doxycycline caused the least staining of teeth, they were clearly 
willing to subject their patients to the risk of a nonfatal condition in 
order to save them from potentially fatal spotted fever. 

Antibiotics proved to be double-edged swords, but their advent at 
the end of World War II had signaled a decline in concern about many 
infectious diseases, especially those, such as Rocky Mountain spotted 
fever, that struck so few victims each year. To be sure, people continued 
to die from spotted fever as well as from other infectious diseases, but 
the American animus against death was largely redirected after World 
War II toward the chronic diseases, especially cancer and heart disease, 
which had been growing as foci of public concern since the 1920s. As 
a result, the 1950s witnessed a dramatic plunge in federal funding for 
research on infectious diseases relative to the rising rate for research 
on chronic diseases. In a 1957 study, for example, Charles V. Kidd 
observed that between 1948 and 1954 the study of communicable 
diseases had dropped from first to eighth place in terms of federal and 
foundation monies allocated for their support. Studies of the endocrine 
system, in contrast, had risen from fifteenth to fourth. Although Kidd 
noted that such classifications of research might be somewhat arbitrary 
and at times influenced by fads, he concluded that the figures confirmed 
"the general opinion that the substance of medical research" had 
"indeed shifted remarkably over the last decade." 

In spite of the facts that more patients visited physicians because of 
infections than for any other group of illnesses and that infections in 
the United States were the primary cause of death in 6 percent of all 
deaths, investigators found funding agencies, whether Congress or 
private foundations, more inclined to support research on chronic 
diseases. Dorland J. Davis, director of the National Institute of Allergy 



spotted Fever after Antibiotics 



225 



and Infectious Diseases from 1964 to 1975, articulated the often un- 
thinking assumptions that plagued infectious disease research. "I recall 
becoming terribly annoyed at a chart that was proposed for showing 
to some influential group— I don't know whether it was Congress or 
another group— which showed the death rates for cancer and heart 
disease going up steeply and the death rate for infectious disease going 
down sharply. I think I got it stopped all right, but ... it took quite 
an effort to get people to think of infectious diseases as still a serious 
health problem.''^^ 

The National Institute of Allergy and Infectious Diseases was the 
categorical incarnation of the former National Microbiological Insti- 
tute. One story, probably apocryphal but nonetheless revealing, held 
that the new name enhanced Congress's willingness to grant the in- 
stitute funds because people continued to die of infectious diseases and 
suffer from allergies, but "nobody ever died of microbiology."^^ Despite 
the new name, a 1965 analysis of federal support for research in 
microbiology found that the field remained significantly undersup- 
ported. Prepared for President Lyndon Johnson as a part of a larger 
review of the NIH, and popularly known as the Wooldridge Committee 
report, the study attributed the situation to several factors, including 
the perception that antibiotics had solved the problem of infectious 
diseases. Another, more difficult problem to attack was the overshad- 
owing of traditional microbiological research by the "glamour and 
scientific status of the flowering field of molecular biology." Although 
agreeing that this new field was undeniably important, the review panel 
believed that its attraction had retarded more traditional studies of 
"host-parasite relationships," the whole field of tropical medicine, and 
medical entomology.^^ 

For rickettsial diseases in particular, major federal funding was pro- 
vided by two agencies. The smaller of the two was the Commission 
on Rickettsial Diseases of the Armed Forces Epidemiological Board, 
one of several commissions supported by the board to maintain ex- 
pertise in particular diseases of military importance, especially in the 
event of atomic warfare. "Despite its name," wrote Paul B. Beeson, 
the board was "primarily a civilian agency." Its Commission on Rick- 
ettsial Diseases, headed first by Joseph E. Smadel and subsequently by 
Charles L. Wisseman, Jr., supported university research on rickettsiae 
through three or four U.S. Army or U.S. Navy contracts each year, 
ranging from $30,000 to $250,000. According to Wisseman, during 
the 1960s these contracts resembled grant awards in support of re- 
spected research programs rather than the more usual military mech- 
anism of quid pro quo service contracts. Meetings of the commission, 



226 



Rocky Mountain Spotted Fever 



furthermore, provided a scientific forum for U.S. rickettsiologists and 
a national meeting at which promising young investigators could be 
recruited. 

The second source of federal funds for rickettsial research was the 
grants program of the National Institutes of Health, especially the 
National Microbiological Institute and its successor institute, the Na- 
tional Institute of Allergy and Infectious Diseases. Between 1946, when 
the grants mechanism began to function, and 1971, when the situation 
began to change somewhat, slightly less than $6 million in grants was 
awarded for research on rickettsial diseases compared to more than 
$526 milhon awarded by the National Microbiological Institute and 
NIAID for all types of extramural research in microbiology, parasi- 
tology, virology, and immunology.^'* This relatively low level of funding 
was due in part to the small number of new researchers coming into 
the field of rickettsiology and in part to a growing emphasis on viral 
and immunological research. New techniques made virology and im- 
munology fruitful fields, and many of the diseases caused by viruses 
and immunological deficiencies had no known treatment. 

Those young investigators who did enter the field of rickettsiology 
generally came from a relatively small number of institutions whose 
interest in rickettsial diseases was historic or had developed during 
World War II. Initially most rickettsial investigators were housed at 
the National Institutes of Health, with rickettsial units at Bethesda, 
Maryland, and at the Rocky Mountain Laboratory in Hamilton, Mon- 
tana; at the military viral and rickettsial unit at Walter Reed Army 
Institute for Research in Washington, D.C; and at Harvard University 
Medical School in Cambridge, Massachusetts, site of the investigations 
of S. Burt Wolbach and Hans Zinsser. The University of Chicago, 
home of Howard Taylor Ricketts, also fostered some rickettsial re- 
search, as did the Rockefeller Institute for Medical Research in New 
York, the locale of Hideyo Noguchi's early work. Investigators trained 
in these centers had also established satellite programs in several uni- 
versities. Henry Pinkerton, for example, studied with Wolbach at Har- 
vard and later moved to Saint Louis University School of Medicine. 
One center of clinical research on Rocky Mountain spotted fever grew 
up in North Carolina, a site of high spotted fever incidence in the east. 
Another became established at the University of Maryland School of 
Medicine in Baltimore, largely as a result of collaboration with the 
unit at Walter Reed in Washington, D.C. Once Q fever had been 
identified as a major problem across the western states, several western 
universities and public health agencies, especially in Texas, Kansas, 
and California, developed expertise in this rickettsial disease. Most of 



spotted Fever after Antibiotics 



227 



the rickettsial investigators who directed these programs during the 
1950s had been trained, of course, in the crucible of wartime work 
with the U.S.A. Typhus Commission." 

NIH grants for rickettsial diseases were inaugurated in 1946, with 
a $7,240 grant to J. A. Montoya of the Pan American Sanitary Bureau 
for an immunological comparison of the Cox and Castaneda typhus 
vaccines. Throughout the 1950s and 1960s, investigators were funded 
for studies of rickettsial epidemiology, for research on immunology 
and serological tests, for the maintenance of rickettsiae in cell Hnes, 
and for the investigation of arthropod vectors. This work was com- 
plemented by the intramural NIAID rickettsial diseases program, lo- 
cated at the RML. With its ever-growing collection of ticks from around 
the world, the RML became an official tick reference center for the 
World Health Organization. 

Basic laboratory research on rickettsiae also prospered. With tech- 
nical advances pioneered during the 1930s and 1940s, investigators 
were able to define the morphology and physiology of rickettsiae more 
precisely. One of the most dramatic new instruments of the early 1940s 
was the electron microscope, which permitted scientists to go beyond 
their limitations under light microscopes in understanding the structure 
of tiny microorganisms.^^ "It is a well recognized principle in natural 
science that understanding of structure is basic to analysis of function," 
wrote Stuart Mudd and Thomas F. Anderson of the University of 
Pennsylvania in a paper on the impHcations of electron microscopy. 
With the light microscope, researchers had not been able to resolve 
the fine structure of bacterial cells or rickettsiae, nor could they visualize 
at all most of the viruses. "Bacteria and rickettsias as examined by 
ordinary bacteriologic methods appear to be simple and structureless," 
Mudd observed in a companion paper, and he cautioned, "The long 
habit of observing such minute and apparently simple objects is often 
reflected in methods of dealing with bacteria in practice as though they 
were much simpler than they actually are."^^ 

The electron microscope provided the first clues to the complex 
structure of rickettsiae, which generally had been grouped with the 
viruses because of their common requirement of intracellular existence. 
In 1943, Harry Plotz and his colleagues published the first electron 
micrographs of rickettsiae in the Journal of Experimental Medicine. 
Comparing the organisms of epidemic and murine typhus, Rocky 
Mountain spotted fever, and Q fever, they found striking similarity in 
the morphological structure of the four types of organisms. The new 
instrument clearly showed that rickettsiae, Hke bacteria, had a limiting 
cell wall distinct from the inner protoplasm. 



228 



Rocky Mountain Spotted Fever 



Furthermore, the electron microscope not only revealed the larger 
rickettsial forms previously studied with the light microscope but also 
rendered visible "smaller coccoidal forms of rickettsiae" identified by 
their limiting membrane and internal structure. These small oval forms 
were of considerable interest, Plotz and his associates stated, because 
they could not be differentiated with certainty from tissue particles by 
ordinary microscopy. "The occurrence of such organisms may throw 
light on the concept of 'invisible forms' of rickettsiae which has been 
brought forward to explain certain experiments in which rickettsiae 
have not been demonstrated in material of known infectivity." The 
detection of rickettsiae invisible under ordinary methods apparently 
elucidated one of the mysteries that had hindered acceptance of the 
organisms as the etiological agents of the typhus-like diseases. Both 
Roscoe R. Spencer and Ralph R. Parker must have welcomed the 
vindication of their findings. In the margin of one copy of their initial 
paper reporting the existence of apparently invisible forms of rickett- 
siae, one anonymous skeptic had written, "Can't see it, can't measure 
it— it doesn't exist."^° 

Stuart Mudd's prophecy that knowledge about the structure of or- 
ganisms would enhance understanding of their function was soon 
reahzed in the case of the rickettsiae. "Since electron microscopy shows 
that the cell walls of bacteria and rickettsias form a relatively small 
fraction of the mass of the cells and since the inner protoplasm may 
be toxic, these facts have practical implications," he observed. "It is 
perhaps not too rash to predict that purified surface antigens will 
increasingly come into use as diagnostic reagents and even as vaccines 
for active immunization."^^ Because there was little impetus to produce 
improved rickettsial vaccines during the 1950s and 1960s, however, 
the use of purified surface antigens— the proteins on the outer cell 
membrane — as laboratory reagents was the most immediate outcome 
of the new knowledge. 

One fruitful line of research, for example, was the more specific 
characterization of rickettsiae. Since 19 16 the Weil-Felix test had pro- 
vided a means for crude distinctions among members of the typhus- 
like disease group, after which cross-protection tests in guinea pigs 
were employed for more precise differentiation. In the 1930s bouton- 
neuse fever had been distinguished from Rocky Mountain spotted fever 
in this way. More sensitive techniques such as the complement fixation 
test, which had been made possible by purified surface antigens, soon 
thereafter revealed that a close immunological relationship existed 
among the rickettsial diseases. 



spotted Fever after Antibiotics 



229 



Information gleaned in such studies eventually generated a new 
classification system that replaced the earlier schemes based on place 
names, geography, or vectors. Regarding the awkwardness of these 
systems, two South African investigators, Adrianus Pijper and C. G. 
Crocker had observed in 1938: "A wit once divided botanical scientists 
into two classes, the lumpers and the splitters. In 1920 the number of 
Rickettsioses for which a separate entity was claimed was three or 
four, and in 1936 the number had risen to well over twenty. Has there 
been too much splitting, and is lumping indicated ?"^^ 

Complement fixation studies permitted rickettsial diseases to be 
lumped into discrete groups displaying similar antigenic properties: 
the typhus group, the tsutsugamushi group, and the spotted fever 
group. The organisms that caused Q fever and trench fever proved so 
antigenically different that each was classified in a wholly separate 
genus. Within the rickettsial genus, the spotted fever group was dis- 
tinguished by a soluble antigen that was group specific and fixed 
complement in the presence of antibodies induced by any other member 
of the group. On this basis the group included all the tick-borne 
rickettsial diseases but also rickettsialpox, which had a mite as its 
vector. Once the soluble antigen had been removed from a specific 
culture of rickettsia by repeated washings, the species-specific antigens 
could be detected. 

This technique also demonstrated that several rickettsiae isolated 
from ticks but apparently nonpathogenic for humans belonged in the 
spotted fever group. The earliest of these "organisms in search of a 
disease," as they were sometimes called, was named Maculatum agent 
in 1939 by Ralph R. Parker, when he and his colleagues first isolated 
it in Amblyomma maculatum ticks. In 1965 this organism was re- 
named Rickettsia parkeri in honor of Parker.^^ Two other nonpath- 
ogenic rickettsiae were identified as members of the spotted fever 
group: Rickettsia montana and the Western Montana U strain of 
Rickettsia rickettsii?^ 

Comparative studies between Rickettsia rickettsii and other path- 
ogenic spotted fever group rickettsiae around the world revealed sur- 
prising relationships. The only one that closely resembled Rickettsia 
rickettsii was Rickettsia sibirica, the agent of North Asian tick typhus, 
a disease first described in the 1930s and found throughout Siberia in 
the Soviet Union, in some localities of China, and in the MongoHan 
Peoples Republic.^^ Another member of the spotted fever group, Rick- 
ettsia australis, caused a disease known as Queensland tick typhus, 
which was first described in 1946 in North Queensland, Australia. 



230 



Rocky Mountain Spotted Fever 



This organism responded immunologically like Rickettsia akari, the 
agent of rickettsialpox.^^ 

In 1965, David B. Lackman, E. John Bell, Herbert G. Stoenner, and 
Edgar G. Pickens at the Rocky Mountain Laboratory proposed that 
the spotted fever group organisms be divided into four subgroups: 

A— Rickettsia rickettsii, and Rickettsia sibirica 

B— Rickettsia conorii and Rickettsia parkeri 

C— Rickettsia akari and Rickettsia australis 

T> — Rickettsia montana and Western Montana U rickettsia'^'^ 

More recent studies, hov^ever, based on comparative analyses of the 
genetic composition of rickettsial organisms, suggest that some tax- 
onomic modifications may be necessary. R. sibirica may be sufficiently 
different from other spotted fever group organisms to occupy a separate 
category, and the genomes of R. rickettsii and R. conorii appear to 
be more closely related than previously believed."^^ 

This line of research has also revealed the existence of other rick- 
ettsial organisms, whose properties have not been explored completely. 
In India, a number of reports between 1943 and 198 1 identified variant 
spotted fever group rickettsiae as causes of Indian tick typhus. Be- 
cause of this disease's mild clinical manifestations, however, most cases 
go unreported, and additional research is needed for more accurate 
identification of the specific rickettsiae involved. In 1985 a possibly 
new, clearly pathogenic rickettsia of the spotted fever group was iden- 
tified in Japan when it caused three cases of exanthemous fever in 
women from a farm area in Anan-shi. Laboratory study ruled out 
tsutsugamushi and confirmed instead an infection of the spotted fever 
group."^^ Variant spotted fever group rickettsiae have also been de- 
scribed in Israel, in Southeast Asia, and in Czechoslovakia. "^"^ They 
may also exist in Africa, but, as in India, because most cases go unre- 
ported, information is more difficult to gather."^^ New nonpathogenic 
spotted fever group rickettsiae also continue to be identified, including 
one in Switzerland and another in the southeast United States."^^ 

By the late 1960s another body of work that utilized new instruments 
and techniques had resolved the ambivalent characterization of rick- 
ettsiae as organisms midway between bacteria and viruses. Within ten 
years after Wendell Stanley crystallized the tobacco mosaic virus in 
1935, other scientists had discovered that viruses were not, as Stanley 
had originally beheved, "autocatalytic proteins." Nucleic acids — de- 
oxyribonucleic acid (DNA) and ribonucleic acid (RNA)— were iden- 
tified as the components of cells that governed life processes, not only 



spotted Fever after Antibiotics 



231 



of viruses but of all living things. Bacteria contained DNA in their 
nuclei and RNA in their cytoplasm. Viruses were show^n to contain 
either DNA or RNA but not both. Although initial research on rick- 
ettsiae had not detected RNA in these organisms, Hans Ris and John 
P. Fox at the Rockefeller Institute demonstrated in 1949 that washing 
procedures used to purify rickettsiae in the early studies had destroyed 
or greatly reduced the RNA in rickettsial cells. Including electron 
micrographs showing distinct nuclear structures in rickettsiae, they 
reported that both DNA and RNA were indeed present in these or- 
ganisms. 

Further buttressing this position was a 1949 study by Marianna R. 
Bovarnick and her mentor John C. Snyder at Harvard University that 
demonstrated independent metabolic activity in rickettsiae — a char- 
acteristic not shared by viruses. Using the Warburg respirometer, a 
device developed in the 1920s by Nobel prize winner Otto Warburg 
for measuring metabolic activity, Bovarnick and Snyder established 
that purified suspensions of epidemic and murine typhus rickettsiae 
exhibited a distinctive respiratory activity, glutamate oxidation. Their 
work provided the impetus to other workers, who further clarified the 
process of rickettsial metabolism and verified that rickettsiae, unlike 
viruses, were also able to perform some reactions necessary for their 
own proliferation.^^ 

Improved tissue culture methods in the 1950s also enhanced studies 
on the morphology and physiology of rickettsiae under controlled 
conditions. The mechanism by which rickettsiae invaded cells was 
studied by Zanvil A. Cohn and his colleagues at Walter Reed Army 
Institute of Research. They concluded that rickettsiae attacked only 
living cells and described conditions necessary for entry to occur. Build- 
ing on Cohn's work, Herbert H. Winkler and EUzabeth T. Miller of 
the University of South Alabama College of Medicine later observed 
that an organism attaches itself to a host cell membrane and "tickles" 
the cell to induce phagocytosis, the process of being taken into a cell. 
Once inside the host cell, rickettsiae grow and multiply with little 
detectable damage to the parasitized cell until it finally ruptures.^^ 

The Walter Reed rickettsial team showed that single cells of Rick- 
ettsia rickettsii divided by transverse binary fission, a bacterial but not 
viral phenomenon. In the course of their work, they had also noted 
that the spotted fever organism sometimes emerged from infected cells 
"by way of long, filamentous microfibrillar structures protruding from 
the edge or surface of the cell." Although the number of rickettsiae 
lost from cells via microfibrils was small, they believed that this mech- 



232 



Rocky Mountain Spotted Fever 



anism deserved "careful consideration" since it might "play an im- 
portant role in dissemination of pathogens, particularly between ad- 
jacent cells."^^ 

By 1969 the body of knowledge so carefully built in these studies 
led to the overwhelming conclusion that rickettsiae were not akin to 
viruses but were instead "highly fastidious bacteria," as Richard A. 
Ormsbee, a specialist in Q fever rickettsiae at the Rocky Mountain 
Laboratory, described them in a review paper. "The importance of 
this conceptual advance" could not be "stressed too strongly," Charles 
L. Wisseman, Jr., of the University of Maryland School of Medicine 
observed some years later, because "it brought to bear on rickettsiology 
the enormous conceptual framework of the science of bacteriology." 
During the 1970s and 1980s, moreover, rapid strides in technology 
unshackled the study of rickettsiae in the laboratory. Improved puri- 
fication methods, simple methods for counting the organisms, and 
better methods for cloning rickettsiae were among the many new 
techniques available. 

Unfortunately, even as these new techniques were being developed, 
it appeared that research interest in rickettsiae and rickettsial diseases 
would not be sustained in the United States. Throughout the 1950s 
and 1960s the numbers of rickettsial investigators had declined stead- 
ily.^^ By 1967 they had become so scarce in the United States that, 
one scientist observed, they had "trouble having a meeting other than 
dinner together."^^ In 1971, moreover, the number of NIH grants for 
rickettsial disease research reached a nadir of between two and five, 
depending on how one counted related subjects. This problem often 
became the focus of discussions at meetings of the Commission on 
Rickettsial Diseases, and two participants in these deliberations sum- 
marized the situation in published articles. Theodore E. Woodward of 
the University of Maryland School of Medicine lamented the lack of 
young people attracted to the field, observing that those researchers 
who still thought about rickettsiae almost every day had "a generous 
display of gray hair." Richard A. Ormsbee cited figures showing that 
when grouped by age, the largest group of rickettsial researchers av- 
eraged 55 years old; the next largest group, 65 years of age. "Only 
four scientists under 40 years of age were in career jobs as rickett- 
siologists in 1971."^^ 

The preservation of rickettsiology as a separate field of inquiry was 
further jeopardized when the military services began reevaluating their 
programs in this area. In 1973 the Armed Forces Epidemiological Board 
disbanded all its commissions, including the Commission on Rickettsial 
Diseases. Because this organization had served as the major national 



spotted Fever after Antibiotics 



233 



forum for rickettsiologists, its demise came as a blow to many in the 
field. The U.S. Army, moreover, shifted its research priorities away 
from rickettsial diseases in general to focus on developing a vaccine 
against scrub typhus, because of that disease's potential military im- 
portance. Likewise, U.S. Navy research emphasis was directed toward 
preparing new vaccines against murine and epidemic typhus. This left 
the National Institute of Allergy and Infectious Diseases in the "awk- 
ward spot," as its deputy director, John R. Seal, later noted, "of being 
the principal Government supporter of rickettsial research but not 
having been given any extra funds to meet this responsibility."^^ 

At NIAID, furthermore, the historic debate over the inclusion of 
medical entomology in the research program had been revived in the 
late 1960s when U.S. involvement in the Vietnam War led to tighter 
budgets for medical research. Institute administrators and the Board 
of Scientific Counselors, an advisory group of distinguished nongov- 
ernmental scientists, intensively examined existing programs as they 
struggled with questions of research priorities in a period of restricted 
growth. The merit of traditional epidemiological and microbiological 
studies of vector-borne diseases also came under scrutiny during this 
period. Because intramural rickettsial and entomological research 
sponsored by NIAID was located at the Rocky Mountain Laboratory, 
the future of this facility became the focus of debate. 

Those who believed that research in medical entomology should be 
abandoned argued that it was more properly supported by the military 
or by the National Science Foundation. In addition, they believed that 
if the institute sought to maintain leadership in medical research, it 
should support promising studies in immunology and in molecular 
biology more substantially than traditional microbiological and epi- 
demiological research. Supporters of the opposing position argued that 
medical entomologists afforded expertise nowhere else available to 
physicians around the world who needed aid in identifying vectors of 
unknown diseases. Time and again, the U.S. experience with scrub 
typhus during World War II was cited as an example of the kind of 
unknown arthropod-borne diseases that the country might encounter 
if drawn into a war in tropical regions.^' 

By the late 1970s tight budgets and staff reductions impelled NIAID 
administrators to revise institute priorities for the intramural program. 
At the end of the decade, medical entomology was discontinued at the 
Rocky Mountain Laboratory and the historic tick collection shipped 
to the Smithsonian Institution. The RML was reorganized into three 
laboratories, only one of which continued the traditional research 
program, and the facility was renamed the Rocky Mountain Labo- 



234 



Rocky Mountain Spotted Fever 



ratories. Under the auspices of the NIAID extramural program, how- 
ever, a variety of grants and contracts for rickettsial disease research 
continued to be funded, and, indeed, virtually all university research 
on rickettsiae received NIAID support/^ 

In addition to these changes, in the early 1970s commercial biologies 
houses in the United States had discontinued production of specific 
rickettsial antigens for diagnostic tests. Although the Centers for Dis- 
ease Control continued to supply these antigens to state health lab- 
oratories and to other designated diagnostic centers, the decline in 
demand for such services v^as reflected in the relatively few institutions 
equipped to make the tests. Reliance on the broad-spectrum antibiotics 
had virtually halted efforts to improve laboratory tests. Routine lab- 
oratory diagnosis, Richard A. Ormsbee noted, was "no better in 1972 
than it was at the close of World War II in 1945." He warned that 
"biomedical competency in rickettsial diseases" in the United States 
would be "largely lost within the next 10 years if these trends con- 
tinue." Ormsbee also described a parallel situation in Western Europe. 
"Laboratories in Brussels, Paris, Rome, London, and Zurich, which 
once maintained vigorous programs of rickettsial research stimulated 
by the occurrence during World War II of Balkan grippe (Q fever) in 
Yugoslavia and Greece and by epidemic typhus in Egypt and Italy, 
now are mainly devoted to other subjects." Conversely, the well-staffed 
laboratories of "Bratislava, Bucharest, and Moscow" continued to 
support research on rickettsial diseases vigorously.^^ 

Given the steady erosion in the numbers of young investigators and 
a persistent sense that rickettsial diseases posed Httle threat to the 
United States, it is doubtful whether any individual could have swayed 
institutional priorities on behalf of rickettsiology by virtue of rhetoric 
alone. What did help to reinvigorate the state of rickettsial research 
in the United States was an unexplained natural phenomenon: in the 
1970s the incidence of Rocky Mountain spotted fever in the United 
States began to rise inexorably. 

In 1959, Joseph E. Smadel had warned that changing population 
patterns, especially the creation of suburban housing developments 
near large east coast cities, might generate a rise in the incidence of 
spotted fever. Noting that this region was an endemic area of the 
disease, Smadel cautioned prospective suburbanites not to forget the 
existence of "islands of infection" of Rickettsia rickettsii, which or- 
dinarily were maintained in "silence" between ticks and the small 
animals on which they fed. "Maryland provides an example in point 
through its projected urbanization of the countryside around Baltimore 
and Washington." Even before the upturn in cases was documented. 



spotted Fever after Antibiotics 



2.35 



RATE 

e oe- 

0 55- 




0 05- 

0 00— 1 

1855 1000 \ OOB <O-0 1875 ioe0 1O8S 

V C AP 

Reported cases of Rocky Mountain spotted fever per 100,000 population, 
by year, in the United States, 1955-83. This graph reveals the surprising 
increase in Rocky Mountain spotted fever that w^as first observed in 1969. 
(Reproduced from D. B. Fishbein, J. E. Kaplan, K. W. Bernard, and W. G. 
Winkler, "Surveillance of Rocky Mountain Spotted Fever, United States, 
1981-1983," Morbidity and Mortality Weekly Report, CDC Surveillance 
Summaries 33 [1984]: 15SS— 18SS.) 



Smadel's prediction appeared prescient to many who monitored the 
incidence of the disease. In 1965 a group of researchers concluded 
that the true incidence of Rocky Mountain spotted fever was actually 
"much greater than the number of reported cases." By 1970 the num- 
bers were clearer. Michael A. W. Hattwick at the Centers for Disease 
Control noted that reported cases in the United States had increased 
from 200-300 per year during the 1950s to 498 in 1969. The case 
fatality ratio also showed "a small but definite rise" since i960. Most 
of these cases were identified in the southeast, while the number of 
cases in the west remained low. By 1977, 1,115 cases were reported 
in the United States, 42 of which were fatal. Among the states most 
afflicted, North Carolina, Virginia, Tennessee, Maryland, and Okla- 
homa headed the list.^° 

In 1970 the rise in spotted fever cases stimulated the Centers for 
Disease Control to initiate a surveillance program that reexamined the 
epidemiology and clinical features of spotted fever. The first five years' 
data gathered from this study confirmed that, although a problem 



Rocky Mountain Spotted Fever 



existed, it had not yet reached the proportions of the pre-antibiotic 
era. In the southeast the incidence of spotted fever reached 12 per 
miUion in 1974, one-sixth of the 76 per miUion recorded in the Rocky 
Mountain states in 1935. The death-to-case ratio, moreover, remained 
betvs^een 5 and 10 percent, less than half the national average before 
antibiotics were introduced. Epidemiologists at the Centers for Disease 
Control reported that, since i960, spotted fever cases had been re- 
ported from every state except Alaska, Hawaii, Wisconsin, Maine, 
and Vermont. Suggesting that a change in population patterns might 
account for the increase, they also speculated that physicians might 
be recognizing the disease more frequently than in the past, and they 
postulated that a cyclic change in the tick vector or the microorganism 
itself could be involved. 

Coming after a period of complacency about infectious diseases, the 
increasing incidence of spotted fever seemed unusual to many epide- 
miologists. Some attributed it to a gradual invasion of the eastern 
United States by Rickettsia rickettsii from the Rocky Mountain regions. 
Others postulated that the western R. rickettsii had gradually, and for 
unknown reasons, become avirulent for humans. In 1977, Willy Burg- 
dorfer at the Rocky Mountain Laboratory dismissed these theories as 
having no scientific merit. Historically, he pointed out, spotted fever 
in the Rocky Mountain regions was "an occupational disease among 
people settling in enzootic areas." Once the land was cleared and 
cultivated, tick infestation decreased, and with it, the incidence of 
spotted fever. In uncultivated western territories that remained heavily 
populated with tick-infested rodents, Burgdorfer observed, people con- 
tinued to contract the disease when, during a short pleasure or business 
outing, they became "part of the ecologic cycle of R. rickettsii.'" In 
contrast, spotted fever in the east had traditionally been "characterized 
by high incidence among children and women — a phenomenon related 
to infestations of household pets, particularly dogs, with the vector 
tick." The shift of eastern populations into natural foci of spotted fever 
and the creation of wooded recreational areas out of previously cul- 
tivated land, Burgdorfer concluded, adequately explained the increas- 
ing incidence of the disease in the eastern United States. 

Ecological factors might account for the increase in incidence of 
spotted fever, but as new studies charted the epidemiology of the 
disease, a few surprises emerged. Overall figures were consistent with 
earlier patterns. Nearly two-thirds of the cases occurred in children 
under fifteen years old, and 61 percent of the patients were male. Only 
52 percent of fatal cases were in young people, but 74 percent were 
in male patients. The lower death-to-case ratio in female patients, 



spotted Fever after Antibiotics 



237 



especially in those aged fifteen through forty-four, was not explained 
by differing rates of rash or tick bite — an unexpected finding. It sug- 
gested that "a degree of protection against fatal Rocky Mountain 
spotted fever" might be afforded women "during their reproductive 
years. "^^ Most peculiar was the relatively high 13.9 percent mortality 
among black male victims. It was more than double the 5.8 percent 
recorded for white males. This racial difference, CDC epidemiologists 
found, was not a function of age. They believed that this "very high" 
death-to-case ratio in black males, especially in those younger than 
ten, could be explained in part by the difficulty of observing a rash in 
dark-skinned patients. Another factor, they suggested, might be the 
more Hmited access to medical care available to poorer blacks in the 
United States. This analysis was consonant with the social concerns 
of the early 1970s, but, as we shall see in chapter 12, a more basic 
physiological process was involved. 

In 198 1 the number of cases of Rocky Mountain spotted fever in 
the United States peaked at 1,192, a national incidence of 51 cases 
per million people. Beginning in that year, Oklahoma became the state 
having the highest incidence of cases in relation to its population, 410 
per million, and its neighbors Texas and Arkansas also reported an 
increased incidence of cases. Despite the high incidence, Oklahoma 
recorded only 397 cases between 1981 and 1983, while heavily pop- 
ulated North Carolina, the state with the greatest number of cases, 
reported 736 during this period. South Carolina with 288 cases and 
Virginia with 238 cases were the third and fourth most infected states 
in the early 1980s. The entire "cycle" of increased cases appeared to 
be hmited to the United States, for no reports were received of this 
phenomenon in other western hemisphere countries. 

Across the Atlantic Ocean, however, a similar increase in tick-borne 
rickettsioses was also observed and first reported in 198 1 by Vittorio 
Scaffidi, an Italian rickettsial researcher located in Palermo, Sicily. 
Between World War II and the mid 1970s, he noted, cases of rickett- 
sioses of all kinds had been reduced to "mere sporadic episodes." Since 
1975, however, several regions of Italy, including Lazio, Liguria, Sicily, 
and Sardinia, had registered "an extraordinary epidemiological event." 
Boutonneuse fever, the spotted fever group disease prevalent through- 
out the Mediterranean basin, had increased from about 30 cases per 
year to 864 cases in 1979. Scaffidi believed, moreover, that the actual 
number of cases was underreported in the region. He speculated that 
ecological changes involving the tick vectors of boutonneuse fever 
"must be presumed. "^^ 

Although Scaffidi noted that this phenomenon had not been reported 



238 



Rocky Mountain Spotted Fever 



elsewhere in the Mediterranean basin, investigators in other Mediter- 
ranean countries soon pubHshed additional accounts of the unusual 
increase. From Israel came reports that from six cases documented in 
1973, the numbers had swelled to sixty-three by 1978.^^ In July 1982, 
Ferran Segura and Bernat Font wrote to the editor of Lancet to report 
an increase in Spain of the disease, which was known there as Med- 
iterranean spotted fever. A total of seventeen cases had met their clinical 
and serological criteria; case distribution had increased from two in 
1978 to six in 198 1. The increase had been confirmed by other hospitals 
in the same area, and most cases came from urban areas. Perhaps, 
they speculated, this reflected a known increase in the number of pet 
animals among city dwellers. "Clearly the resurgence in Mediterranean 
Spotted Fever seen in Italy is also happening in Spain," they wrote, 
and they suggested that indeed it was "a pattern common to the whole 
geographical area in which this disease is endemic."^^ 

This unusual increase in tick-borne rickettsial disease stimulated 
renewed research in the Mediterranean countries and led as well to 
fruitful international collaborations.^^ The Sicilian group, for example, 
led by Scaffidi's colleagues Serafino Mansueto and Giuseppe TringaH, 
began studying boutonneuse fever's epidemiology in western Sicily and 
the persistence of antibodies to R. conorii in humans and in dogs. In 
the 1930s dogs had been shown susceptible to infection with tick- 
borne rickettsial diseases. They also, of course, could bring infected 
ticks into the homes of their human owners. All of this research 
revealed that although the basic pathological physiology of the tick- 
borne rickettsial diseases had been described, much remained unknown 
in the last decades of the twentieth century about their natural histories. 

Diagnosis of Rocky Mountain spotted fever also continued to be 
difficult in atypical cases, a situation underscored in a 1977 tragedy 
at the Centers for Disease Control in Atlanta, Georgia. In mid February 
Robert Dubington, a building custodian, and George Flowers, a ware- 
houseman, both of whom worked in the same building at the CDC, 
were hospitalized with symptoms of high fever, nausea, diarrhea, and 
vomiting. Mental confusion and convulsions followed, but no rash 
was observed. Flowers died on 27 February, and Dubington died two 
days later, on i March. Initially, Legionnaires' disease, the mysterious 
bacterial malady that had struck unexpectedly in 1976 and was under 
investigation at the CDC, was suspected in these deaths. Post-mortem 
studies, however, revealed that both men had died from Rocky Moun- 
tain spotted fever. It remained unclear how they contracted the disease, 
for neither had routine access to laboratory areas. 

Plainly this disease, thought "conquered" in 1948, retained the abil- 



spotted Fever after Antibiotics 



239 



ity to wreak misery and death. The resurgence of Rocky Mountain 
spotted fever in the United States thus accompHshed what rickettsial 
investigators had been unable to achieve by exhorting their colleagues. 
A new generation of investigators, many of whom were too young to 
recall the pre-antibiotic era, were challenged to apply their training in 
immunology, in molecular biology, and in other new fields to the 
problem of Rocky Mountain spotted fever. By 1980 a new professional 
organization, the American Society of Rickettsiology and Rickettsial 
Diseases, had been formed. Junior and senior rickettsiologists col- 
laborated in reexamining diagnostic tests, vaccines, chnical knowledge, 
and therapy. In this task, they could draw on the body of basic research 
accumulated since World War II that provided information about rick- 
ettsial organisms essential to formulating new strategies against the 
disease. 



Chapter Twelve 



Mysteries Explained, 
Mysteries Remaining 



All interest in disease and death is only another expression of 
interest in life. 

Thomas Mann, The Magic Mountain 



"The easiest way to lose ground in the fight against infectious dis- 
eases," wrote Harry DowHng in 1977, "is to assume that they have 
been conquered and nothing more needs to be done."^ The dangers 
of such neglect became obvious in relation to Rocky Mountain spotted 
fever during its surprising upsurge in the 1970s. Although a number 
of advances in understanding the basic biology of rickettsiae had been 
made since World War II, virtually no new methods of diagnosis, 
prevention, or therapy had been developed. This situation suggests 
that, in the United States, active programs of research on any disease 
are difficult to sustain without the stimulus of an imminent disease 
threat. In examining the recent history of spotted fever, however, it is 
also clear that rapid advancement in applied fields since 1970 largely 
depended upon the advances in basic research fields made during 
spotted fever's quiescent decades between 1950 and 1970. Efforts to 
control and combat this disease of nature are still under way, and any 
definitive evaluation of these endeavors will require a longer historical 
perspective. Several long standing mysteries raised by spotted fever 
have been solved, however, and those that remain suggest directions 
for future inquiry. 

When spotted fever began to increase during the 1970s, renewed 
chnical studies of the disease confirmed older assessments of the grave 
danger posed by infections with Rickettsia rickettsii. Circulatory col- 
lapse, kidney failure, and neurological damage were all potential 
threats. Since 19 19, when S. Burt Wolbach published his major review 
of the disease, spotted fever had been understood as an affliction of 
the circulatory system. From the 1940s through the 1960s, occasional 



240 



Mysteries Explained, Mysteries Remaining 



241 



papers had discussed specific cardiac complications of spotted fever 
and their treatment. At the end of the 1970s, however, new research 
indicated that the disease did not cause significant loss of heart function. 
The greater danger appeared to be the threat to the circulatory tree, 
as had been suggested in World War 11.^ 

In contrast to an early appreciation of spotted fever's effect on the 
circulatory system, it was not until the 1950s that its full potential 
impact on the brain was appreciated. In 1947 a physician in Ann 
Arbor, Michigan, had queried the editor of the journal of the American 
Medical Association about long-term neurological effects from spotted 
fever. The Journal's editor had restated the position taken at that time 
by most textbook authors. Headache, hearing loss, lethargy or rest- 
lessness, mental confusion, and sometimes delirium characterized the 
disease during the acute course, but these afflictions were expected to 
last only a few weeks. ^ Later studies disputed this conclusion, noting 
that infection with Rickettsia rickettsii could destroy the myelin sheath 
around nerves and cause the formation of granulomatous tissue in the 
brain."^ "Pathologic examination reveals greater damage to the brain 
in spotted fever than in any other rickettsial disease," concluded one 
group of investigators in 1952.^ 

In its most severe form, spotted fever may mimic other diseases, 
especially acute appendicitis. The pathological physiology of these 
abdominal symptoms is not yet understood, but, as the authors of 
another recent paper noted, they "underscore the protean manifes- 
tations" of spotted fever.^ The mechanism by which the organism 
damages human cells is also just beginning to be understood. "Evidence 
is accumulating," wrote David H. Walker of the University of North 
Carolina School of Medicine at Chapel Hill in 1982, "that injury occurs 
to the cell membrane on penetration into and release from the host 
cell by rickettsiae."^ 

During the 1970s, Walker and his colleagues initiated a variety of 
studies on Rocky Mountain spotted fever because of their location in 
North Carolina, an endemic spotted fever area reporting a large num- 
ber of cases each year. During and after World War II, the state's high 
incidence had spurred George T. Harrell, Jerry K. Aikawa, and their 
colleagues at the Bowman Gray School of Medicine of Wake Forest 
University in Winston-Salem to conduct studies on clinical problems 
associated with the disease, especially capillary permeability and fluid 
loss. A clinical review paper written by Harrell in 1949 stood for 
decades as definitive in clinical practice, and in 1966, Aikawa published 
a monograph on spotted fever that summarized much of this work.^ 



242 



Rocky Mountain Spotted Fever 



Walker's group continued this North Carohna tradition, focusing es- 
pecially on clinical and epidemiological studies. 

One problem they solved, for example, was the mystery of high 
spotted fever mortality in black males, a phenomenon noted in 1976 
by epidemiologists at the Centers for Disease Control. Two tentative 
explanations had been offered at that time: the difficulty of identifying 
a typical spotted fever rash on dark skin and diminished access to 
medical care, a problem common to lower socioeconomic groups. 
Neither rationale proved satisfactory, because black females, who 
shared both criteria, exhibited a mortality rate no higher than did 
white females. The figures instead suggested. Walker and his colleagues 
believed, the existence of some sex-linked genetic condition that oc- 
curred primarily among blacks and rendered males more vulnerable. 
It was known that about 12 percent of American black males suffered 
from a glucose-6-phosphate dehydrogenase (G6PD) deficiency, a ge- 
netic-linked metabolic disorder much less common in whites and in 
black females. The North Carolina group therefore studied the fre- 
quency of G6PD deficiency among black males who died from spotted 
fever and, indeed, found that the incidence was much higher than 
expected. "Ultimately," they concluded, "G6PD-deficient persons may 
represent a target population for an effective vaccine against Rocky 
Mountain spotted fever."^ 

In addition to black males with a G6PD deficiency, several other 
groups of people at high risk were identified as potential candidates 
for vaccination against spotted fever. One large cluster was comprised 
of children and adults living in highly infected districts, especially those 
with existing medical problems that might become hfe-threatening 
under the strain of a severe infection. Army recruits training in "tick 
belt" states made up another population at risk.^° Laboratory per- 
sonnel, although a relatively small group, were often exposed to highly 
virulent strains of spotted fever, as the fatal cases sustained by many 
early laboratory martyrs attested (see Table 4). The two 1977 deaths 
at the Centers for Disease Control, moreover, prompted a letter to the 
editor of the New England Journal of Medicine in support of vaccine 
development for the protection of laboratory workers. Even before 
this tragedy, other concerned scientists had published a number of 
studies on the risks of laboratory infection. 

When the 1970s increase in spotted fever cases renewed interest in 
protective vaccination, however, the only vaccine available was the 
Cox yolk sac product, which had been produced virtually unchanged 
by Lederle Laboratories since the 1940s. The first clear indication that 
the state of spotted fever prophylaxis was unacceptable came in 1973, 



Mysteries Explained, Mysteries Remaining 



2.43 



TABLE 4. Deaths from Laboratory- Acquired Spotted Fever 
Infections 



Year 



Name 



Position 



1912 Thomas B. McClintic 

1918 Stephen MoHnscek 

1919 Arthur H. McCray 
1922 WilHam E. Gettinger 
1924 George Henry Cowan 

1928 Albert LeRoy Kerlee 

1927 Elisabeth Brandt 

1931 Kokyo Sugata 

1932 Masajiro Nishibe 

1935 Jose Lemos Monteiro 

1935 Edison de Andrade Dias 

1942 Hector Calderon Cuervo 

1977 Robert Dubington 

1977 George Flowers 



Passed Assistant Surgeon, U.S. Public 
Health Service 

Laboratory assistant to Hideyo Noguchi, 
Rockefeller Institute for Medical 
Research 

Bacteriologist, Montana State Board 
of Health 

Student assistant, U.S. Public Health 
Service 

Field assistant, Montana State Board of 
Entomology and U.S. Public Health 
Service 

Student assistant, U.S. PubHc Health 
Service 

Laboratory technician for Max 
Kuczynski, Berlin 

Assistant to Norio Ogata, Chiba Medical 
College, Japan 

Professor, Niigata Medical College, 
Japan 

Brazilian investigator, Butantan Institute, 
Sao Paulo, Brazil 
Monteiro's assistant 
Investigator in Bogota, Colombia 
Building custodian, U.S. Centers for 
Disease Control 

Warehouseman, U.S. Centers for Disease 
Control 



when a seven-member team of researchers led by Herbert L. DuPont 
at the University of Maryland School of Medicine in Baltimore tested 
stored samples of the Spencer-Parker tick tissue vaccine and com- 
mercially produced Cox yolk sac vaccine. Groups of volunteers from 
the Maryland House of Correction in Jessup, Maryland, w^ho had been 
informed of the risks involved and advised that they could w^ithdraw 
from the study at any time, w^ere inoculated with one of the vaccines 
or left unvaccinated as controls. Subsequently each was injected with 
a large dose of virulent R. rickettsii. All developed cases of Rocky 



244 



Rocky Mountain Spotted Fever 



Mountain spotted fever and were treated. The results of this test were 
unequivocal: neither type of spotted fever vaccine prevented the dis- 
ease. 

This finding would not have been surprising to the original producers 
of those vaccines, whose own studies revealed that they lessened the 
severity of infection rather than preventing it. In the 1920s and 1930s 
when the Spencer-Parker and Cox vaccines were developed, human 
trials with virulent organisms were unthinkable, because no therapy 
existed that could cure a severe case of the disease. Instead, the vaccines 
had been tested in experimental animals for efficacy, purity, and po- 
tency. After the development of broad-spectrum antibiotics, the need 
for any vaccine seemed minimal, and no work had been done to 
improve the existing product. 

About the time the DuPont study was published, Richard H. Kenyon, 
WiUiam M. Acree, George G. Wright, and Fred W. Melchoir, Jr., 
members of the U.S. Army Medical Research Institute of Infectious 
Diseases at Fort Detrick in Frederick, Maryland, reported that they 
had prepared a new candidate vaccine against Rocky Mountain spotted 
fever. Using R. rickettsii propagated in tissue cultures of chick embryo 
cells rather than in the chick embryos themselves, the group prepared 
two vaccines for testing in guinea pigs. The first was irradiated to kill 
the rickettsiae, a procedure based on recent studies with tularemia and 
psittacosis organisms indicating that vaccines killed by ionizing ra- 
diation retained greater antigenicity than those killed by heat or chem- 
icals. The second vaccine was treated with formaldehyde to kill rick- 
ettsiae. Initial tests on guinea pigs demonstrated that both cell culture 
vaccines were more than nine hundred times as active as the old yolk 
sac vaccine. Surprisingly, the vaccine prepared with formaldehyde 
proved superior to the irradiated vaccine in protecting guinea pigs 
from direct challenge with R. rickettsii. Over the next few years, the 
army group worked to improve the formaldehyde cell culture vaccine 
by various techniques and to conduct initial tests of its efficacy in 
animals and safety for humans. 

In October 1976, however. Congress withdrew all funds for the 
army's spotted fever vaccine program, arguing that it duplicated re- 
search efforts at the National Institute of Allergy and Infectious Dis- 
eases. Shortly thereafter, WiUiam S. Augerson, commanding general 
of the U.S. Army Medical Research and Development Command, wrote 
to the NIAID director, Richard Krause, requesting that "NIAID assume 
responsibility for completion of qualifications necessary to license this 
RMSF vaccine for human use." After reviewing the proposed vaccine's 
promise, the potential population that would benefit from vaccine 



Mysteries Explained, Mysteries Remaining 



2-45 



development, and the program's cost, Robert Edelman, chief of the 
Chnical Studies Branch in NIAID's Microbiology and Infectious Dis- 
eases Program, won concurrence from the director of the program, 
WiUiam Jordan, to recommend that the institute sponsor the work.^^ 

On 30 October 1978 the NIAID Microbiology and Infectious Dis- 
eases Advisory Committee considered plans for testing the candidate 
vaccine. Samuel L. Katz, chairman of the Department of Pediatrics at 
Duke University Medical Center, urged the committee to go forward 
with clinical trials of the candidate army vaccine. "Because our state 
reports the largest number of cases each year of any throughout the 
nation," Katz stated, "we have come to speak of the disease as North 
Carolina Tick Typhus." Buttressing the case that a large potential 
population for the vaccine existed, Katz noted that North Carolina 
physicians actually treated 1,524 cases of suspected spotted fever each 
year, in contrast to the 200 cases they reported to the CDC.^^ 

The advisory committee agreed that the program should continue, 
but it recommended that before any direct human trials were con- 
ducted, two other studies should be done. "A careful and intense 
epidemiologic study was needed to clearly determine the incidence and 
importance of the disease and to define populations in which the 
usefulness of the vaccine in preventing disease in humans might later 
be determined." In addition, the committee recommended that a pri- 
mate model be developed in order to study "the nature of the disease, 
the immune response to infection and the safety, immunogenicity and 
efficacy of candidate vaccines."^" 

Reasons for such a cautious approach were articulated by John R. 
Seal, NIAID deputy director. Noting the relatively small size of the 
population that would seek protection from a new spotted fever vac- 
cine. Seal noted that few commercial laboratories were likely to be 
interested in producing it. "Here we seem to be on a track of a limited 
use vaccine which, under present law, would have to be dispensed by 
the CDC under IND [investigational new drug] regulations." More 
importantly. Seal was concerned about whether the new vaccine would 
be any more effective than the old Cox vaccine, which lessened the 
severity of the disease but did not prevent it.^^ 

The recommended preliminary studies were implemented, and the 
epidemiologic data provided somewhat surprising results. Catherine 
M. Wilfert at Duke University Medical Center led a team of researchers 
in identifying cases of spotted fever that could be serologically con- 
firmed in two North CaroHna counties. In contrast to the estimates 
by physicians that many more cases occurred than were reported, 
Wilfert and colleagues found that only one of three reported cases 



Rocky Mountain Spotted Fever 



exhibited antibodies in the blood. Although no primate model was 
developed for broad studies on the nature of spotted fever infection, 
the candidate vaccine w^as tested in guinea pigs. Results indicated that 
it protected them only partially from infection w^ith virulent R. rick- 
ettsii. As with the older vaccines, higher doses and frequent booster 
injections increased protection. 

The ambiguities in these findings raised questions about the vaccine's 
probable efficacy as well as the number of people who might benefit 
from it. Ten years of research had been invested in the product, how- 
ever, and in 1983 a placebo-controlled double-blind study in humans 
was conducted by a group led by Mary L. Clements at the Center for 
Vaccine Development of the University of Maryland School of Med- 
icine in Baltimore. Of the fifty-two volunteers vaccinated, sixteen were 
challenged with virulent R. rickettsii one month after vaccination. Six 
unvaccinated volunteers also received the challenge dose as controls. 
The results of this test were only marginally better than in the DuPont 
study. Twelve of the sixteen vaccinated volunteers developed typical 
Rocky Mountain spotted fever, as did all the controls. As with the 
earlier vaccines, the incubation period was longer, the duration of 
constitutional symptoms shorter, and the height of fever lower in the 
vaccinated volunteers. "The vaccine provided only partial protection 
against Rocky Mountain spotted fever," concluded the investigators. 

The failure of this new vaccine to provide complete protection 
against spotted fever dashed the hopes of anyone seeking vaccination 
against the disease. In 1980, while the army vaccine was still being 
developed, a U.S. Food and Drug Administration panel comprised of 
leading rickettsiologists, pediatricians, and virologists had evaluated 
the efficacy and safety of Lederle Laboratories's yolk sac vaccine. Citing 
the 1973 DuPont study, the members of the Food and Drug Admin- 
istration panel expressed little confidence in the product's efficacy. 
They noted that between 1969 and 1972 there had been no complaints 
about its safety; however, they observed, this "probably indicated more 
the failure to report complaints than inherent safety." The panel 
awarded the vaccine "an unfavorable benefit/risk ratio," and assigned 
it category III-A status, which meant that it could remain commercially 
available pending completion of additional tests. The decision, how- 
ever, was moot. On 11 June 1979, even before the panel met, Lederle 
Laboratories had requested that its license to produce spotted fever 
vaccine by the yolk sac method be revoked and had withdrawn the 
product from the market.^^ 

It is likely that both the caution of the Food and Drug Administration 
panel and the decision of Lederle Laboratories were influenced by 



Mysteries Explained, Mysteries Remaining 



^47 



more than dispassionate scientific inquiry. By the 1970s the pubhc had 
become more wiUing to sue commercial producers of vaccines when 
products failed or caused toxic side effects. Because U.S. law placed 
financial responsibility on vaccine producers for the statistically pre- 
dictable number of injuries and deaths that occur from widespread 
vaccination programs, firms such as Lederle often reduced their liability 
by halting production of products considered risky. When the number 
of potential vaccine recipients was small, as in the case of Rocky 
Mountain spotted fever, commercial advantage was completely over- 
shadowed by considerations of liability. Even though no suit had been 
brought over Lederle's spotted fever vaccine, the company's swift ac- 
tion reflected a larger problem that has yet to be resolved. 

The groups involved in assessing the failure of the old yolk sac and 
new tissue culture vaccines arrived at the same conclusion about why 
neither provided full protection. Basing their evaluations on new dis- 
coveries in immunology made during the preceding decades, the FDA 
panel, the DuPont group, and the Clements group speculated that the 
humoral immunity stimulated by the vaccines was insufficient to pro- 
vide full protection against the disease. Although additional research 
on the immune response in spotted fever infections must be done before 
conclusive proof can be presented, they suggested that recovery from 
a frank spotted fever infection probably produced immunity mediated 
by cellular rather than by humoral mechanisms, because there was no 
correlation between the presence of antibodies in serum and protection 
from the disease. 

Although these two types of immunity had been known since the 
late nineteenth century, detailed knowledge about their components, 
mechanisms, and interactions had only begun to be elucidated in the 
1960s. The humoral immune system, named from the historic usage 
of the word humors for body fluids, was shown to function through 
the actions of specialized white blood cells, called B cells, which pro- 
duce antibodies against foreign antigens on the surface of invading 
organisms. Circulated throughout the blood and other body fluids, 
these antibodies are most effective against bacteria, their toxins, and 
viruses present in body fluids. The cell-mediated immune system, com- 
prised of other white blood cells, especially those known as T cells, 
works in addition to the humoral system. The T ceUs do not produce 
antibodies, but they coordinate attacks by several other types of white 
cells against cancer cells, transplanted tissue, and intracellular bacteria 
and viruses. Rickettsia rickettsii, of course, falls into the last category. 

These concepts helped to explain another longstanding mystery of 
spotted fever and possibly pointed the way toward a more successful 



Rocky Mountain Spotted Fever 



vaccine. Howard Taylor Ricketts had first attempted to treat spotted 
fever victims with immune serum taken from people or animals that 
had recovered from a spotted fever infection. All such immune sera 
failed to effect the dramatic cures possible when diphtheria patients 
were treated similarly. Diphtheria, of course, is caused by the action 
of a toxin, which is rapidly rendered harmless by the antibodies present 
in immune sera. Spotted fever rickettsiae, in contrast, inhabit the cells 
of the host, where they are protected from antibody attack. 

Because both the Spencer-Parker and the Cox spotted fever vaccines 
had utilized killed rickettsiae, furthermore, they may not have stim- 
ulated cell-mediated immunity as did recovery from an active case of 
the disease. In contrast, a number of vaccines against viral diseases 
such as rabies, yellow fever, and poHo were prepared from attenuated — 
that is, weakened but not killed— strains of virus. Such products mim- 
icked active infection and produced cell-mediated immunity without 
the risk of severe disease. Howard Taylor Ricketts had attempted 
without luck to attenuate the spotted fever organism early in the 
century, and after the development of the Spencer-Parker vaccine, 
further efforts to attenuate the organism had been abandoned. 

Between 1974 and the mid 1980s, several groups of investigators 
launched projects aimed at designing a vaccine to produce the complete 
protection stimulated only by frank infection with the disease or by 
a successful attenuated vaccine. Using a variety of techniques de- 
veloped by molecular biologists, they first focused .on identifying in- 
dividual surface proteins of Rickettsia rickettsii that might serve as 
antigens in an improved vaccine. In reviewing this work, Hui Min 
Feng, Celia Kirkman, and David H. Walker at the University of North 
Carolina School of Medicine observed that one series of these studies 
produced a "reasonable catalogue" of approximately thirty-five rick- 
ettsial proteins. Another group of studies utilized monoclonal anti- 
bodies and the methods of immunoblotting and radioimmunoprecip- 
itation to analyze these proteins as antigens. 

Gregory A. McDonald, Robert L. Anacker, and Kareen Garjian at 
the Rocky Mountain Laboratories cloned the gene for one of these 
antigens in Escherichia coli bacteria and tested the effectiveness of the 
recombinant-DNA product as a vaccine against Rocky Mountain spot- 
ted fever. They reported that the material protected mice from a lethal 
dose of virulent R. rickettsii. Although this candidate vaccine faces 
years of refinement and testing, it may prove to be the hoped-for 
effective and safe preventative against spotted fever.^^ 

Since no vaccine is available at present, and since relatively few 
people at occasional risk of contracting spotted fever would be vac- 



Mysteries Explained, Mysteries Remaining 



249 



cinated in any case, the key to effective therapy is rapid diagnosis. The 
increase in spotted fever incidence during the 1970s also stimulated a 
renewed interest in diagnostic tests, which, like the vaccine, had not 
been significantly improved since World War 11. As late as 1976, for 
example, Charles C. Shepard and his associates at the Centers for 
Disease Control stated flatly, "No laboratory diagnostic procedure is 
now available that will provide a specific laboratory diagnosis in time 
to help the physician in his decision about therapy" in suspected spotted 
fever cases. ^" 

In 1978 another CDC study— this one on the characteristics most 
frequently associated with fatal Rocky Mountain spotted fever— re- 
iterated the need for more accurate diagnostic tests. Delay in seeking 
treatment proved not to be an important factor associated with dying 
from spotted fever. The high fever and debility accompanying the 
disease sent most patients to a physician at about the same time. The 
average amount of time that elapsed between the onset of illness and 
the initiation of appropriate therapy, however, was more than two 
days longer for fatal than for nonfatal cases. When patients who later 
died first visited a physician, the study noted, they rarely displayed the 
classic diagnostic triad of fever, rash, and history of tick bite. Instead, 
they presented nonspecific symptoms, such as fever, headache, and 
malaise, which were characteristic of several diseases. Gastrointestinal 
complaints, including nausea, vomiting, abdominal pain, and diarrhea, 
were also prominent symptoms in approximately one-third of the fatal 
cases and were present in only 4 percent of those who recovered. 
Because of these puzzling initial symptoms, the critical history of 
whether the patient had been bitten by a tick was obtained three days 
later among fatal cases than it was from those who recovered. In short, 
those patients who were treated with an antirickettsial broad-spectrum 
antibiotic within the first five days of illness usually recovered, while 
all but two of the fatal cases studied were not treated before the sixth 
day of illness. "The major problem in diagnosis appears to be the 
presence of nonspecific or misleading symptoms occurring before onset 
of rash," the authors concluded. 

What was clearly needed was a laboratory test that, no matter what 
symptoms were present, could rapidly demonstrate whether the patient 
was infected with R. rickettsii}^ In their search for such a test, inves- 
tigators in the 1970s first reviewed the research of previous decades, 
hoping to find leads to exploit. In the early 1950s, R. Shin-man Chang, 
Edward S. Murray, and John C. Snyder at the Harvard University 
School of Public Health had discovered that sera from spotted fever 
patients as early as six days after the onset of illness agglutinated 



250 



Rocky Mountain Spotted Fever 



human group O erythrocytes, or red blood cells, after the erythrocytes 
were sensitized with substances extracted by ether from suspensions 
of infected yolk sac membranes. This diagnostic test, called the indirect 
hemagglutination (IHA) test, proved more sensitive and technically 
simpler than the complement fixation test. Very little active material 
was required— enough could be prepared from one infected yolk sac 
to test at least five hundred sera. This procedure, however, had never 
been developed commercially. It had not been found superior to the 
complement fixation test, and because of the generally low level of 
interest in spotted fever during the 1950s, the older technique had 
remained the standard laboratory procedure. ^° 

Nearly two decades later, with spotted fever on the rise, several 
investigators sought to improve the IHA test. One group introduced 
the use of stabilized sheep erythrocytes so that the test could be per- 
formed under field conditions. Another team adapted the test to mi- 
crotiter plates and employed the technique known as sucrose density 
gradient centrifugation to purify antigen from R. rickettsii. With these 
changes, the IHA test provided positive results in a greater percentage 
of cases than did the complement fixation test.^^ The microagglutina- 
tion test, developed in 1969, and the latex agglutination test, developed 
in 1980, provided two additional variations on this technique. The 
microagglutination test is sensitive, but because it requires large 
amounts of rickettsial antigen, it has remained primarily a research 
tool. The latex agglutination test, which is simple, quick, and requires 
no elaborate instrumentation, is now commercially available. 

Another promising approach to diagnosis took advantage of the 
abihty to "label" antibodies with fluorescent or radioactive material 
or with enzymes. To test for the presence of R. rickettsii^ antibodies 
labeled with fluorescent dye are added to a patient's serum on a glass 
slide and allowed to react. After being washed to remove any unat- 
tached antibodies, the slide is examined under an ultraviolet light, 
which renders visible any labeled antibodies attached to the rickettsiae. 
If no rickettsiae are present, all the labeled antibodies are washed 
away, and no fluorescence is seen. Before this technique was adapted 
for diagnosis of spotted fever, it had been widely used in research 
laboratories. As early as 1950, A. H. Coons and his colleagues used 
a fluorescence technique to describe rickettsiae in the human body 
louse. In i960 and 1961, Willy Burgdorfer and David B. Lackman 
adapted the technique to identify Rickettsia rickettsii in tissues of 
infected ticks and guinea pigs.^^ In the mid 1970s, antibody labeling 
was employed for laboratory diagnosis of spotted fever. Variations of 
the technique have produced direct and indirect immunofluorescence 



Mysteries Explained, Mysteries Remaining 



tests, a microimmunofluorescence test, and an enzyme-linked immu- 
noabsorbent assay.^"^ Studies of the new tests have demonstrated that 
their sensitivity is significantly greater than the old Weil-Felix and 
complement fixation tests. 

In the late 1970s, two groups reported the development of the most 
rapid diagnostic test yet available. A team from Fort Detrick and the 
University of Maryland led by Theodore E. Woodw^ard found that as 
early as the fourth day of illness, a skin biopsy of any suspect rash 
could be tested v^ithin four hours by the indirect immunofluorescence 
test. David H. Walker and his associates at the University of North 
Carolina School of Medicine adapted the direct fluorescent antibody 
technique for the skin biopsy method. Both techniques w^ere demon- 
strated useful in diagnosing suspected cases of spotted fever.^^ 

Although all of these nev^ tests promised quicker, more sensitive, 
and more reUable results than the old complement fixation test, none 
of them. Walker observed in a 1982 review^ paper, could be relied on 
by the practicing physician for the diagnosis of acute spotted fever. 
Unless a rash had already developed from w^hich a skin biopsy could 
be taken— and many fatal cases of spotted fever show^ed no rash in 
the early stages— patients usually lacked sufficient antibody levels for 
laboratory tests to be useful. Just the previous year, however. Walker 
and his colleagues had identified eschars in spotted fever patients. These 
small, dark scabs covering the site where an infected tick had attached 
were characteristic of many rickettsial infections, but they had been 
considered notably absent in Rocky Mountain spotted fever. Although 
eschars in spotted fever might continue to be unusual events, the 
researchers noted, their potential existence could prove helpful in di- 
agnosis. In addition to assisting clinical diagnosis, a biopsy of the 
eschar might reveal the presence of rickettsiae before the skin rash 
appeared. 

At present, rapid diagnosis of Rocky Mountain spotted fever depends 
primarily on a physician's awareness that a patient might be at risk 
to contract the disease. Especially in geographic areas where spotted 
fever is rarely seen, a medical history that includes questions about 
recent travel in areas where ticks are prevalent may be the principal 
clue. To alert both physicians and the public to the dangers of the 
disease, a variety of media has been utilized by state health agencies 
in highly infected areas. In Virginia, for example, a public education 
program keyed to the theme "Virginia's Hidden Enemy" includes 
newspaper articles, television and radio announcements, brochures 
aimed at practicing physicians, and posters located in schools and 
other public places. Such efforts are especially useful to visitors from 



Rocky Mountain Spotted Fever 




Willy Burgdorfer of the Rocky Mountain Laboratories became one of the 
leading investigators of spotted fever during its surprising upsurge in the 
1970s. His contributions included an explanation of v^hy the disease had 
been limited to the west side of the Bitterroot River and the discovery of 
the organism that causes Lyme disease— a serendipitious offshoot of spotted 
fever research. (Courtesy of the Rocky Mountain Laboratories, NIAID.) 



noninfected areas, who are often unaware that a disease known as 
Rocky Mountain spotted fever might pose a threat outside the western 
states. 

Another widespread misconception about spotted fever is that chil- 
dren are the only group likely to contract it. Having more contact 
through outdoor play with wooded areas and with dogs harboring 
ticks, children between the ages of five and nine certainly incur the 
largest number of cases. As a group from the Bureau of Epidemiology 
of the Centers for Disease Control noted in 1982, however, it is adult 
victims between the ages of forty and fifty-nine who are the most likely 
to die, once infected. Again, the key to recovery is rapid diagnosis, 
and, unfortunately, physicians who treat adults are less likely to rec- 
ognize symptoms as rapidly as pediatricians, most of whom have seen 
numerous cases among their patients. "It has been my twenty-year 



Mysteries Explained, Mysteries Remaining 



253 



long experience," Willy Burgdorfer commented, however, "that once 
a physician loses a patient to spotted fever, he v^ill not lose a second 
one, because death from spotted fever is an unnecessary loss of life."^^ 

Burgdorfer had studied Rickettsia rickettsii, as well as numerous 
other organisms, since coming to the Rocky Mountain Laboratory in 
the 1950s from Switzerland. In the early 1980s his research on one 
longstanding mystery relating to Rocky Mountain spotted fever pro- 
duced the spin-off solution to another mystery in an ancillary field, 
the discovery of the organism that caused Lyme disease. First identified 
in Old Lyme, Connecticut— hence its name— this disease caused a 
characteristic bull's-eye rash, followed by a variety of symptoms, in- 
cluding arthritis, heart complications, and neurological disorders. In- 
vestigators at Yale University, particularly Allan Steere, had discovered 
that Lyme disease responded to penicillin treatment, but the etiologic 
agent remained unidentified until Burgdorfer traveled to New York to 
search for ticks infected with R. rickettsii along the northeast coast. 

Twenty-five to fifty cases of spotted fever occurred each year in this 
area, but R. rickettsii had never been isolated from local ticks. In 1979, 
Burgdorfer joined forces with Jorge L. Benach of the New York State 
Department of Health in a concerted effort to solve the puzzle. In 
areas where spotted fever had been contracted, Benach and Burgdorfer 
collected several thousand Dermacentor variabilis ticks— the common 
dog tick usually associated with the disease in the east. To test the 
ticks, Burgdorfer employed a "hemolymph" test he had developed in 
1970 that allowed quick determination of the presence of rickettsiae. 
One leg of a tick was amputated and a drop of hemolymph from the 
wound placed on a microscopic slide. When stained by the Gimenez 
method, rickettsiae were easily visible under the microscope. Positive 
specimens could then be subjected to fluorescent antibody studies to 
identify the particular rickettsial group to which the organisms be- 
longed. This technique itself was a quantum leap from the older meth- 
ods of injecting tick contents into guinea pigs and waiting to see 
whether they developed fever."^^ 

Of the thousands of ticks tested, "not a single one was found to 
have R. rickettsii^'' Burgdorfer noted, although "about 15 percent of 
them were infected with a nonvirulent type [of rickettsial, R. montana.'' 
Thinking that perhaps they were investigating the wrong tick, Benach 
collected several hundred ticks of the species Ixodes dammini, which 
were usually parasites of deer but were more numerous in the area 
than the dog tick. He sent them to Burgdorfer, who examined them 
at the RML for rickettsiae. They, too, were all negative. "But in two 
ticks I found a microfilaria," Burgdorfer said in an interview, after 



254 



Rocky Mountain Spotted Fever 



which he smiled and noted, "Here comes the serendipity." Having 
found the earHer developmental stage of a similar microfilaria in Ixodes 
ticks in Sv^itzerland during a sabbatical year in 1978, Burgdorfer began 
dissecting the two ticks very carefully, "tissue by tissue." He found 
no more microfilariae, but instead he found spirochetes. Burgdorfer 
knew^ that spirochetes had been considered as the possible cause of a 
European disease similar to Lyme disease, and he also knew that 
spirochetes were sensitive to penicillin, the drug that had been used 
successfully to treat Lyme disease victims. "I put two and two together 
and was convinced I had discovered the etiologic agent of Lyme dis- 
ease." By 1982 serological and laboratory work had confirmed his 
hunch, and the organism was named in his honor, Borrelia burg- 
dorferi."^^ 

Reflecting the circuitous route by which scientific discovery often 
occurs, Burgdorfer's research had produced the answer to a problem 
totally unrelated to his initial work. The existence of virulent R. rick- 
ettsii in New York ticks, in fact, still has not been demonstrated. Other 
spotted fever mysteries long ignored, however, have yielded to intense 
study during the 1970s and 1980s. One line of research explained the 
phenomenon of reactivation, first noted in 1922 by Roscoe R. Spencer 
and Ralph R. Parker. At that time they experienced a scientific epiphany 
when they realized that the spotted fever organism was nonvirulent 
in flat ticks and virulent in engorged ticks. Spencer's experiments had 
revealed that either a blood meal or warming could produce a similar 
reactivation of virulence in R. rickettsii, but he was at a loss to explain 
the mechanism by which the process occurred. During the 1950s, 
Marianna R. Bovarnick and E. G. Allen demonstrated that metabolic 
changes produced by low temperatures affected the virulence of typhus 
rickettsiae. Winston H. Price and J. H. Gilford further characterized 
the reactivation phenomenon, showing that virulent R. rickettsii could 
be made avirulent by treatment with PABA. This process could be 
reversed, moreover, by incubation with particular coenzymes. In 
1967, Emilio Weiss and his colleagues confirmed these findings and 
showed that R. rickettsii possessed metabolic requirements similar to 
R. prowazekii.'^'^ 

In 1982, Stanley F. Hayes and Burgdorfer elucidated the specific 
physical characteristics that accompanied the metabolic changes of 
reactivation in R. rickettsii. Using the electron microscope, they de- 
scribed two structures in the organism that underwent profound al- 
teration as it changed in virulence. The "microcapsular layer" was an 
outer structure of the organism, readily identified in electron micro- 
scopic examinations of engorged ticks. Around it was the "slime layer," 



Mysteries Explained, Mysteries Remaining 



2.55 



which formed a "discrete electron-lucent zone" around the organism. 
In starved ticks "neither the microcapsular layer nor slime layer remains 
a discrete entity. Instead, they are shed and form stringy, shredded, 
and somewhat flocculent strands." Incubation at 37°C or feeding of 
starved infected ticks resulted in the restoration of these structures, 
and, as a corollary, the pathogenicity and virulence of the organism. 
Continuing study of the reactivation phenomenon may yield clues 
about the organism's pathogenic mechanism and about why it does 
so httle damage to its tick host.^^ 

In contrast to a satisfactory intellectual explanation for this mystery, 
the ecology of Rickettsia rickettsii— what Ralph R. Parker always 
called the disease's natural history — remains only partially understood. 
Research in this area has been based on a conceptual model articulated 
in the 1950s by a Soviet parasitologist, E. N. Pavlovsky. The geographic 
areas in which specific infections occurred, Pavlovsky suggested, were 
characterized by well-defined ecological peculiarities determined by 
topography, climate, vegetation, and other environmental factors. In 
such natural foci, the pathogens, their vectors, and vertebrate hosts 
formed a nidus, or biologically balanced ecological system. Only when 
humans unwittingly stumbled into this system did the pathogens be- 
come a hazard. J. R. Audy of the Institute for Medical Research in 
Kuala Lumpur, Malaya, colorfully summarized Pavlovsky's theory at 
a 195 8 meeting of the Royal Society of Tropical Medicine and Hygiene 
at Manson House in London. "A man does not look for lion in a rain 
forest, nor for rhododendrons in a chalk-pit, because it is known that 
their preferred habitats are different from these." Pathogenic organisms 
similarly prefer different kinds of environments, and one principal 
difficulty in studying the biosystems of particular organisms, Audy 
maintained, was the human tendency to concentrate thought "on clin- 
ical disease in man, rather than on the pathogen in its natural envi- 
ronment." This has confused the picture greatly, "for the distribution 
of a pathogen is wider than that of disease caused by it and the latter 
cannot be understood without understanding the former as a whole." 
In an effort to enhance their understanding of biosystems inhabited 
by rickettsiae, Soviet and eastern bloc investigators have initiated an 
active program of field research. A rational method for controlling 
diseases based on environmental principles is the long-term goal of 
the work.^"^ 

Even before Pavlovsky gave voice to his theory, the peculiarities of 
several rickettsial diseases had already stimulated investigators in the 
United States to consider the natural histories of the organisms. The 
reason that scrub typhus attacked some troops and spared others 



Rocky Mountain Spotted Fever 



during World War II, for example, was explained by its natural oc- 
currence in particular foci, the so-called islands of infection. Even older 
was the enigma of why Rocky Mountain spotted fever had been limited 
to the west side of the river in the Bitterroot Valley. All sorts of guesses 
had been ventured, from the unwillingness of ground squirrels to cross 
the river to analyses of the vegetation on each bank. In 198 1, Willy 
Burgdorfer, Stanley F. Hayes, and Anthony J. Mavros at the Rocky 
Mountain Laboratory addressed the problem anew. Proceeding on the 
initial hypothesis that genetic variations in Dermacentor andersoni 
ticks on the east and west sides of the river might result in differences 
of susceptibility to infection with R. rickettsii, they collected large 
numbers of ticks from each area for study. Burgdorfer's hemolymph 
test was used to identify east side ticks containing rickettsiae; larvae 
from those female ticks showing none were allowed to engorge on 
male guinea pigs. Surprisingly, although none of the guinea pigs de- 
veloped fever, some of them showed low titers of antibodies to R. 
rickettsii when tested a month later. "This suggested," the authors 
noted in their paper, that some of the larvae were infected with "an 
ovarially-acquired rickettsia" that was not detected by hemolymph 
testing."^^ 

Subsequent dissection confirmed their suspicions. In "large percen- 
tages" of the negative ticks— up to 80 percent of those from some east 
side locations, a spotted fever group rickettsia, which was given the 
name East side agent, was identified in specific tissues, especially the 
ovaries. In one test, female ticks from the east side were fed on guinea 
pigs infected with virulent R. rickettsii and allowed to lay their eggs. 
Those females whose ovaries were heavily infected with the East side 
agent showed no R. rickettsii in their ovaries, although it was present 
in all other tissues. Their eggs, moreover, contained only the East side 
agent— R. rickettsii had not been transmitted. This "interference phe- 
nomenon," by which the East side agent prevented the establishment 
of virulent R. rickettsii in the ovaries of east side ticks offered one 
explanation of why spotted fever was limited to the west side of the 
river. "Indeed," wrote the investigators, "it may provide a logical 
answer to the questions why in certain localities . . . virulent strains 
of R. rickettsii are rare or have never been established.""^^ 

From the beginning of spotted fever investigations in 1902, when 
the tick-borne nature of the disease was first postulated, investigators 
had sought to understand and describe its maintenance in nature. Early 
spotted fever investigations were strongly influenced by work on other 
vector-borne diseases that had mammalian hosts thought to be their 
natural reservoirs. Such an animal reservoir was assumed to exist for 



Mysteries Explained, Mysteries Remaining 



^S7 



Rocky Mountain spotted fever, and the earliest investigations had 
identified the Columbian ground squirrel and other small rodents as 
likely candidates. Once Howard Taylor Ricketts had demonstrated 
that the spotted fever organism could be transmitted through the eggs 
of the female tick to later generations, however, the tick itself was also 
viewed as a major disease reservoir. 

In 19 1 6, just after spotted fever had been identified in eastern Mon- 
tana, Ralph R. Parker pubHshed the disturbing finding that immature 
stages of the spotted fever tick, Dermacentor andersoni, fed on rabbits, 
a potentially huge natural reservoir of the disease. Over the next three 
decades, Parker continued his research, assisted by several young en- 
tomologists who carried on the work after his death. They identified 
the rabbit tick Haemaphysalis leporis-palustris, which rarely bit hu- 
mans, as a vector of one strain of R. rickettsii, and they carefully 
mapped the geographical locale of this tick and its major host, Syl- 
vilagus nuttallii, more commonly known as Nuttall's cottontail."^^ For 
several decades entomologist WilHam L. Jellison championed the the- 
ory that cottontails were probably the major reservoir of Rocky Moun- 
tain spotted fever in the United States. In 1980, however, he came out 
of retirement to join a younger generation of researchers in reopening 
the question. "The relationship in the U.S. between cottontail rabbits 
and several species of Dermacentor ticks, including the main vectors 
of the spotted fever agent, R. rickettsii, is recognized, and the close 
agreement in the distribution of cottontails to spotted fever cases in 
certain geographic areas cannot be disputed," the group reported. 
"However, our observations do not support the hypothesis that cot- 
tontail rabbits are the primary reservoirs of Rickettsia rickettsii in 
nature."^^ 

Small rodents were also investigated as potential natural reservoirs 
of spotted fever. Early research by William Colby Rucker, Lunsford 
D. Fricks, and S. Burt Wolbach had indicated that the meadow 
"mouse"— or more precisely, a meadow vole—Microtus modestus was 
not susceptible to infection. In 1934, however, JelHson demonstrated 
that these and other small rodents not only could be infected but also 
could transfer the infection to feeding nymphal ticks. Although this 
research suggested that rodents might play a role in the maintenance 
of the infection in nature, Jellison was not able to recover rickettsiae 
from animals in the wild. Twenty years later, however, Douglas J. 
Gould and Marie L. Miesse at the Walter Reed Army Medical Center 
confirmed Jellison's prediction. They recovered spotted fever group 
rickettsiae from the tissues of a meadow vole, Microtus pennsylv aniens, 
during a study in suburban Alexandria, Virginia. Their study did not 



258 



Rocky Mountain Spotted Fever 



indicate the actual prevalence of spotted fever among v^ild meadow^ 
voles, nor did it determine the role played by these mammals in the 
maintenance of spotted fever in nature. Additional research on small 
animal reservoirs and their tick vectors by Willy Burgdorfer and his 
colleagues during the 1960s pointed out the complexity of the problem, 
w^hich will not easily be solved. ^° 

In 1935, Ralph R. Parker had also raised the question of cycles in 
the occurrence of spotted fever, an observation that w^ould prove pre- 
scient in the late 1960s w^hen the disease began increasing in the United 
States for no identifiable reason. Parker's data on the yearly incidence 
of spotted fever in seven western states showed peaks of incidence in 
19 1 5, 1922, and 1929, which suggested a seven-year cycle. What 
caused this cycle, however, was not clear. Variations in the number of 
persons exposed, in tick abundance, and in the percentage of ticks 
carrying virulent organisms might all contribute to such a phenomenon. 
Parker also acknowledged that there were probably "even more fun- 
damental" influences underlying these cycles. As two examples of this, 
he cited factors that benefited or harmed the hosts of each stage of 
the tick and meteorological conditions affecting the portions of the 
tick life cycle spent in estivation or hibernation. "The possible factors 
that affect the degree of virulence of the virus in ticks in nature, and 
which consequently determine whether it will cause frank or inapparent 
infections, are not understood. . . . That such factors are certainly 
involved, however, is shown by evidence" such as variations in wild 
ticks' ability to produce recognizable infections in laboratory animals 
some years and not in others. 

This line of research was continued after World War II as funds and 
interest permitted. In 1961, for example, a Virginia health officer, 
F. J. Spencer, pubhshed the results of data on the incidence of Rocky 
Mountain spotted fever and tularemia in Virginia between 1949 and 
1958. His data indicated that 68.4 percent of the 588 cases of spotted 
fever occurred east of Virginia's western mountains. Within this eastern 
area, moreover, six counties in south-central Virginia reported 16.3 
percent of the spotted fever cases and 25.7 percent of the tularemia 
cases. Spencer suggested that these figures represented Pavlovsky's 
concept of the nidality of disease and argued that they might indicate 
synergism between tularemia and spotted fever in this focal area.^^ 

Another study, conducted by a group of investigators led by Verne 
F. Newhouse at the Centers for Disease Control, used sophisticated 
statistical analysis to examine ten geographic and sociologic variables 
in each of the 159 counties of Georgia in an attempt to determine how 
they were correlated with the occurrence of spotted fever. Through 



Mysteries Explained, Mysteries Remaining 



259 



techniques known as principal-component analysis and cluster anal- 
ysis, the group identified four geographically similar areas in Georgia 
that exhibited different incidences of spotted fever. The disease was 
low in the south and in the "upper north," moderate in the central 
region, and high in the "lower north." The most important variables, 
they found, were climate and geography — factors that annually en- 
hanced or diminished tick populations. Of secondary but still major 
importance, they discovered, were the changes wrought during the 
fifteen-year period by humans on the environment. These changes 
included suburban development and the reclamation of wooded land 
for recreational purposes. ^'^ 

Such recent ecological studies of spotted fever underscore the earliest 
observations about the disease, that it is a place disease, a disease of 
nature. Because of its generational transmission in ticks. Rocky Moun- 
tain spotted fever will probably never be eradicated. Unlike its close 
relative epidemic typhus, however, spotted fever does not represent a 
smoldering threat that could rapidly become a large-scale killer in time 
of war. A number of questions remain unanswered, and neither lab- 
oratory diagnosis nor prevention is ideally reliable. Nonetheless, Rocky 
Mountain spotted fever is curable and, in conjunction with public 
education programs, a manageable disease. The measures employed 
against spotted fever through the decades since it was first identified 
have reflected both the facility and the limitations of medical research 
during the twentieth century. As the number of martyrs to laboratory- 
acquired spotted fever suggests, however, this disease has been and 
remains a dangerous adversary. The history of Rocky Mountain spot- 
ted fever thus stands not only as a tribute to organized inquiry in the 
medical sciences but also as a reminder that, because humans and 
microorganisms share the earth's biosystem, vigilance against infec- 
tious diseases must continually be maintained. 



Abbreviations 



cc 

MSBE 

MSBE, First Biennial Report 
MSBE, Second Biennial Report 
MSBE, Third Biennial Report 
MSBE, Fourth Biennial Report 
MSBE, Fifth Biennial Report 
MSBE, Seventh Biennial Report 
MSBE, Eighth Biennial Report 
MSBE, Ninth Biennial Report 
MSBH 

MSBH Minutes 



Correspondence of Robert A. Cooley 
during his tenure as secretary of the 
Montana State Board of Entomology, 
17 bound volumes, Montana State 
Archives, Helena 

Montana State Board of Entomology 

Montana State Board of Entomology, 
First Biennial Report, 191^—1914 
(Helena, 191 5) 

Montana State Board of Entomology, 
Second Biemiial Report, 191^—1916 
(Helena, 1917) 

Montana State Board of Entomology, 
Third Biennial Report, 
(Helena, 1919) 

Montana State Board of Entomolog>', 
Fourth Biennial Report, i^i^i^zo 
(Helena, 192 1) 

Montana State Board of Entomology, 
Fifth Biennial Report, i^iz—i^z^ 
(Helena, 1924) 

Montana State Board of Entomolog)', 
Seventh Biennial Report, 191J-1918 
(Great Falls [1929]) 

Montana State Board of Entomology, 
Eighth Biennial Report, i^z^ip^o 
(Great Falls [193 1]) 

Montana State Board of Entomology, 
Ninth Biennial Report, ipji-ip^z 
(Helena [1933]) 

Montana State Board of Health 

Minutes of the Montana State Board 
of Health, Montana State Archives, 
Helena 



261 



262 

MSBH Records 

MSBH, First Biennial Report 

MSBH, Second Biennial Report 

MSBH, Third Biennial Report 

MSBH, Fourth Biennial Report 

MSBH, Tenth Biennial Report 

NARA, Saint Louis 
NIAID 

MAID files, NIH Historical 
Office 

NIH 

NLM 

PH-MHS, Annual Report (year) 



Abbreviations 

Montana State Board of Health 
Records, Record Group 28, Montana 
State Archives, Helena 

Montana State Board of Health, First 
Biennial Report of the Montana State 
Board of Health from Its Creation 
March ij, ipoi to November 50, 
1^02 (Helena, [1903]) 

Montana State Board of Health, 
Second Biennial Report of the 
Montana State Board of Health from 
December i, 1^01 to November 30, 
1904 (Helena, [1905]) 

Montana State Board of Health, Third 
Biennial Report of the Montana State 
Board of Health from December i, 
1904 to November 50, 1906 (Helena, 
[1907]) 

Montana State Board of Health, 
Fourth Biennial Report of the Montana 
State Board of Health and First 
Biennial Report of the State Registrar 
of Births and Deaths, 1907 and 1908 
(Helena, [1909]) 

Montana State Board of Health, Tenth 
Biennial Report of the Montana State 
Board of Health for the Years 1919- 
1910 (Helena, [192.1]) 

Federal Records Center, National 
Archives and Records Administration, 
Saint Louis, Missouri 

National Institute of Allergy and 
Infectious Diseases 

Vertical file of information on the 
history of Rocky Mountain spotted 
fever and on the National Institute of 
Allergy and Infectious Diseases, 
National Institutes of Health Historical 
Office, Bethesda, Maryland 

National Institute(s) of Health 

National Library of Medicine 

U.S. Treasury Department, Public 
Health Service, Annual Report of the 
Surgeon General of the United States 
Public Health and Marine Hospital 



Abbreviations 



263 



PHS Records 



Ricketts Papers 



RML, Annual Report (year) 

RML, Monthly Report, 
(month and year) 

RML Research Records 



RML Scrapbook 
(period indicated) 

ZEA 



Service (Washington, D.C.: 
Government Printing Office, annual 
publication, 1902-12) 

Records of the U.S. Public Health 
Service, Record Group 90, National 
Archives and Records Administration, 
Washington, D.C. 

How^ard Taylor Ricketts Papers, 
Department of Special Collections, 
Joseph Regenstein Library, University 
of Chicago, Chicago 

Rocky Mountain Laboratory, Annual 
Report^ Rocky Mountain Laboratories, 
Hamilton, Montana 

Monthly reports filed by the director of 
the Rocky Mountain Laboratory (or its 
earlier designations), Montana State 
Archives, Helena 

Research Records of the Rocky 
Mountain Laboratory, Records of the 
National Institutes of Health, Record 
Group 443, National Archives and 
Records Administration, Washington, 
D.C. 

Six Scrapbooks of the Rocky Mountain 
Laboratory, 1919-49, Rocky 
Mountain Laboratories, Hamilton, 
Montana 

Archives of the Department of Zoology 
and Entomology, Montana State 
University, Renne Library, Bozeman 



Notes 



Chapter One: A Twentieth -Century Disease of Nature 

1. James W. Moulder, "The Rickettsias," in R. E. Buchanan and N. E. 
Gibbons, eds., Bergey's Manual of Determinative Bacteriology^ 8th ed. (Bal- 
timore: Williams & Wilkins Co., 1974), 882; S. Stanley Schneierson, Atlas 
of Diagnostic Microbiology (North Chicago: Abbott Laboratories, 1974), 4, 
36. 

2. Tsutsugamushi, or scrub typhus, was known in the Orient at least by 
the sixteenth century. Its history is discussed in chap. 6. 

3. W. C. Rucker, "Rocky Mountain Spotted Fever," Public Health Reports 
27 (I9i2):i47i. 

4. George T. Harrell, "Treatment of Rocky Mountain Spotted Fever with 
Antibiotics," Annals of the New York Academy of Science 55 (i952):io27- 
42. 

5. WilHam D. Tigertt, "A 1759 Spotted Fever Epidemic in North Carohna," 
Journal of the History of Medicine and Allied Sciences 42 (i987):296-304. 

6. Mary A. Newcomb, Four Years' Personal Experience in the War (Chicago: 
H. S. Mills & Co., 1893). I ^ni grateful to Fredrick Hambrecht for bringing 
this reference to my attention. 

7. My discussion of the early history of typhus is based on Hans Zinsser, 
Rats, Lice, and History (Boston: Little, Brown & Co., 1935), and on John 
C. Snyder, "Typhus Fever Rickettsiae," in Frank L. Horsfall, Jr., and Igor 
Tamm, eds.. Viral and Rickettsial Infections of Man, 4th ed. (Philadelphia: 
J. B. Lippincott Co., 1965), 1059-94. 

8. Dale C. Smith, "The Rise and Fall of Typhomalarial Fever: II. Decline 
and Fall," /. Hist. Med. Allied Sci. 37 (i982):287-32i. 

9. See, for example, Erwin H. Ackerknecht, Medicine in the Paris Hospital, 
1J94—1848 (Baltimore: Johns Hopkins Press, 1967); and Erna Lesky, The 
Vienna Medical School in the Nineteenth Century (Baltimore: Johns Hopkins 
University Press, 1976). 

10. William Wood Gerhard, "On the Typhus Fever, Which Occurred at 
Philadelphia in the Spring and Summer of 1836," American Journal of Medical 
Science 19 (1837): 289-92, 298-99, 302—3; Dale C. Smith, "Gerhard's Dis- 
tinction between Typhoid and Typhus and Its Reception in America, 1833- 
1860," Bulletin of the History of Medicine 54 (i98o):368-85. 

11. Rudolf Virchow, "Report on the Typhus Epidemic in Upper Silesia," 
Eng. trans, in L. J. Rather, ed., Rudolf Virchow: Collected Essays on Public 
Health and Epidemiology., 2 vols. (Canton, Mass.: Science History Publica- 
tions, 1985), 2:205-319. 

12. See, for example, Claude Bernard, An Introduction to Experimental 
Medicine, trans. Henry C. Greene (New York: Macmillan Co., 1927); Rudolf 
Virchow, Cellular Pathology, trans. Frank Chance (Philadelphia: J. B. Lip- 
pincott Co., 1863); and Robert Hagelstein, "The History of the Microscope," 
New York Microscopial Society Bulletin 2 (i944):i-i9. 



265 



266 



Notes to Pages p-14 



Chapter Two: A Blight on the Bitterroot 

1. Gretchen Jellison, Introduction, in Bitter Root Valley Historical Society, 
ed., Bitterroot Trails, 2 vols. (Darby, Mont.: Professional Impressions, 1982), 
1:17. In recent years the words Bitter and Root have been combined officially. 
In the early years of the century, the rwo-word form was invariably used. 

2. Samuel Lloyd Cappious, "A History of the Bitter Root Valley to 19 14," 
M.A. thesis. University of Washington, 1939, 1-2. Curiously, Cappious never 
mentions spotted fever. 

3. Peter Ronan, History of the Flathead Indians (Minneapolis: Ross & 
Haines, 1890); John Duffy, The Healers: A History of American Medicine 
(Urbana: University of Illinois Press, 1979), 2—4; idem, "Medicine and Medical 
Practices among Aboriginal American Indians," in Felix Marti-Ibanez, ed.. 
History of American Medicine: A Symposium (New York: MD Publications, 
1959), 15-33- 

4. Duffy, "Medicine and Medical Practices"; Paul C. Phillips, Medicine in 
the Making of Montana (Missoula: Montana State University Press, 1962), 
i; Ronan, History of the Flathead Indians, 13-14; Report of the investigation 
of Louis B. Wilson and William M. Chowning in MSBH, First Biennial Report. 

5. Reuben G. Thwaites, ed.. The Journals of Lewis and Clark, 8 vols. (New 
York, 1905; reprint, New York, Arno Press, 1969), 3:52-57, 5:246; Cappious, 
"History of the Bitter Root Valley," 6-10; Phyllis Twogood, Henry Grant, 
and Lena Bell, "History of Lewis and Clark Expedition in the Bitter Root 
Valley," in Bitter Root Valley Historical Society, ed., Bitterroot Trails 1:37- 
45; Phillips, Medicine in the Making of Montana, 20-31. 

6. L. D. Pricks, "Rocky Mountain Spotted Fever," manuscript, file "S.F. 
History (Manuscript by Dr. Fricks on R.M.S.F.)," p. 2, RML Research Records. 

7. Ibid., 2-3. 

8. Monica G. Shannon, "Catholicity in the Bitter Root Valley," in "The 
Bitter Root Valley Illustrated," magazine suppl. to the Western News, May 
19 10, 35; Cappious, "History of the Bitter Root Valley," 54-61, 65-67; 
Ronan, History of the Flathead Indians, 22-33, 38-41; Phillips, Medicine in 
the Making of Montana, 34-40. 

9. Cappious, "History of the Bitter Root Valley," 11-15, 16-17. 

10. Weekly Missoulian, 28 May and 13 October, 1880, as cited in Robert 
N. Philip, "AJournalistic View of Western Montana, 1870-19 10: Some News- 
paper Items Relevant to the Development of the Bitter Root Valley and the 
Occurrence of Rocky Mountain Spotted Fever," manuscript, 1984, i. Copies 
of this manuscript have been deposited in the Ravalli County Historical Mu- 
seum and the library at the University of Montana. 

11. "The World Famous Valley of the Bitter Root: Its Early History, Its 
Incomparable Resources and the Men Who Have Wrought Mightily in Its 
Development," in "The Bitter Root Valley Illustrated," magazine suppl. to the 
Western News, May 1910, 7; W. B. Harlan, "Pioneer Fruit Growers of the 
Bitter Root," in ibid., 10. Missoula and Cedar Creek Pioneer, 24 November 
1870, and Weekly Missoulian, 20 April 1883, as quoted in Philip, "Journalistic 
View," I, 27. 

12. Missoula Pioneer, 9 December 1871, and Pioneer, 24 August 1872, as 
cited in Philip, "Journalistic View," 3; Ronan, History of the Flathead Indians, 
58-62; Western News, 20 October 1891, as cited in Philip, "Journalistic View," 
67. 



Notes to Pages 14-18 



267 



13. See Philip, "Journalistic View," 18-68. 

14. Ibid., 47, 61. 

15. Western News, 8 April 1896, as cited in Philip, "Journalistic View," 
85. 

16. Philip, preface to "Journalistic View," n.p. 

17. Weekly Missoulian, 11 August 1888, 23 and 30 October 1889, Bitter 
Root Bugle, 24 January, 5 June, 7 and 21 August, 4 and 11 September 1890, 
all as cited in Philip, "Journalistic View," 52, 55, 60. 

18. Phillips, Medicine in the Making of Montana, 268—75. 

19. Weekly Missoulian, 16 April 1880, as quoted in Phillips, Medicine in 
the Making of Montana, 289-90, n. 4. 

20. Ibid., 278, 290, n. 7. There were twenty-seven reported smallpox cases 
in this epidemic. 

21. The diphtheria epidemic was reported in the Weekly Missoulian, 6 March 
1885, and the Indian deaths from apparent tuberculosis in the same paper, 
24 July 1885. Both are cited in Philip, "Journalistic View," 36. 

22. The figure for cases reported in the newspapers was tabulated from 
Philip, "Journalistic View," for each year. The official count was made by 
Wilson and Chowning and is given in their report. See MSBH, First Biennial 
Report, 32-41. 

23. Wilson and Chowning's report, MSBH, First Biennial Report, 28, 30; 
Phillips, Medicine in the Making of Montana, 271. 

24. Reports of two spotted fever deaths in 1 882 are in the Weekly Missoulian, 
10, 17, and 24 March 1882. On 6 July 1883 the paper reported one death 
from spotted fever. See Philip, "Journalistic View," 25, 29. 

25. Phillips, Medicine in the Making of Montana, 164, 167-68. 

26. Ibid., 278-81. 

27. George Rosen, "The Bacteriological, Immunologic, and Chemothera- 
peutic Period, 1875-1950," Bulletin of the New York Academy of Medicine, 
second series, 40 (June 1964) 1487-93. 

28. Erwin H. Ackerknecht, "Anticontagionism between 1821 and 1867," 
Bull. Hist. Med. 22 (1948) 15 62-93. 

29. Phillips, Medicine in the Making of Montana, 423, omits Minshall's 
practice in the Bitterroot. For more complete information on his career, see 
Ravalli Republican, 9 October 1895 and 23 March 1898, Bitter Root Times, 
13 March 1896, Western News, 19 December 1906, all as cited in Philip, 
"JournaHstic View," 83, 86, 96, 155. 

30. An Act to Increase the Efficiency and Change the Name of the United 
States Marine Hospital Service, i July 1902, 32 Stat. L. 712. 

31. MSBH, First Biennial Report, 4, 8. For biographical information on 
Longeway, see Phillips, Medicine in the Making of Montana, 356, 359. 

32. The designations black fever and blue disease are noted in G. T. 
McCullough, "Spotted Fever," Medical Sentinel 10 (July 1902): 225; "black 
typhus fever" is noted in several sources, including the Bitter Root Times, 24 
June 1893, cited in Philip, "Journalistic View," 75. 

33. The diagnosis of "typhoid pneumonia and measles" was reported in 
the Daily Missoulian, 11 May 1896, as cited in Philip, "JournaHstic View," 
86; McCullough noted that "the new Standard dictionary" and "text books 
of authority" identified spotted fever as cerebrospinal meningitis or cerebro- 
spinal fever, and Journal of the American Medical Association reported in 



z6S 



Notes to Pages 18—20 



1902 an epidemic of spotted fever in Montana that was identified as cere- 
brospinal meningitis. See McCuUough, "Spotted Fever," 225; "The 'Spotted 
Fever' Epidemic," JAMA 38 (1902): 13 13. Spotted fever was identified as a 
cognomen for typhus as well as for cerebrospinal meningitis in William Osier, 
The Principles and Practice of Medicine (New York: D. Appleton & Co., 
1892), 39, 9^- 

34. McCuUough stated that the disease was also known in Idaho and Alaska. 
See his "Spotted Fever," 225. 

35. For biographical information on Wood see James F. Hammarsten, "The 
Contributions of Idaho Physicians to Knowledge of Rocky Mountain Spotted 
Fever," Transactions of the American Clinical and Climatological Association 
94 (i982):28-29, 33-41. 

36. Marshall W. Wood, "Spotted Fever as Reported from Idaho," U.S. War 
Department, Report of the Surgeon General of the Army to the Secretary of 
War, 1896 (Washington, D.C.: Government Printing Office, 1896), 60. 

37. On Wood's attack of spotted fever, see Edward E. Maxey, "Rocky 
Mountain Spotted Fever. A Summary of Progress," exerpts from speech given 
3 August 193 1, in Notebook "RMSF— Idaho— Early History," Notebooks of 
Ralph R. Parker (hereafter cited as R. R. Parker Notebooks, RML Research 
Records). 

38. Wood, "Spotted Fever," 61, 63. 

39. Edward E. Maxey, "Some Observations on the So-called Spotted Fever 
of Idaho," Medical Sentinel 7 (October 1899) 143 3-3 8 (quotations from p. 
434). 

40. Ibid., 436. For additional information about the history of spotted fever 
in Idaho, see W. O. Spencer, "Mountain or Spotted Fever, as Seen in Idaho 
and Eastern Oregon," Medical Sentinel 15 (i907):532-37; "The Present Status 
of Rocky Mountain Spotted Fever in Idaho," in "Rocky Mountain Spotted 
Fever," Montana State Board of Health Special Bulletin no. 26 (i923):27- 
28; Notebook "RMSF— Idaho— Early History," R. R. Parker Notebooks, 
RML Research Records. 

41. "Tick-borne Infections in Colorado," abstract in JAMA 94 (1930):! 172; 
J. M. Braden, "Some Observations on Four Cases of Spotted Fever Occurring 
in Colorado," Colorado Medicine 3 (i9o6):2i3— 19; Notebook, "RMSF— 
Colorado— Early History to 1929," R. R. Parker Notebooks, RML Research 
Records; Frederick D. Strieker, "The Prevalence and Distribution of Rocky 
Mountain Spotted Fever in Oregon," in "Rocky Mountain Spotted Fever," 
Montana State Board of Health Special Bulletin no. 26 (i923):i8-20 (quo- 
tation from p. 18); Notebook "RMSF— Oregon— Early History to 1925," 
R. R. Parker Notebooks, RML Research Records. 

42. Albert B. Tonkin, "Incidence of Rocky Mountain Spotted Fever in 
Wyoming," in "Rocky Mountain Spotted Fever," Montana State Board of 
Health Special Bulletin no. 26 (i923):23-27; Notebook "RMSF— Wyoming- 
Early History to 1926," R. R. Parker Notebooks, RML Research Records. 

43. On Washington, see A. U. Simpson, "Rocky Mountain Tick Fever in 
the State of Washington," in "Rocky Mountain Spotted Fever," Montana State 
Board of Health Special Bulletin no. 26 (i923):20-23. On California, see 
F. L. Kelly, "Rocky Mountain Spotted Fever: Its Prevalence and Distribution 
in Modoc and Lassen counties, California: A Preliminary Report," California 
State Journal of Medicine 14 (i9i6):407-9; F. L. Kelly, "Rocky Mountain 
Spotted Fever in California," Pub. Health Rep. 31 {1916)11'/ 4; J. G. 



Notes to Pages 11-24 



Gumming, "Rocky Mountain Spotted Fever in California," Journal of Infec- 
tious Diseases 21 (i9i7):509-i4; Notebook, "RMSF— California — Early His- 
tory to 1929," R. R. Parker Notebooks, RML Research Records. On Utah 
and Nevada, see A. A. Robinson, "Rocky Mountain Spotted Fever, w^ith Report 
of a Case," Medical Record 74 (i9o8):9i3-22; "RMSF — Utah — Early History 
to 193 1," and "RMSF— Nevada — Early History to 1928," R. R. Parker Note- 
books, RML Research Records. 

44. Daily Missoulian, 5 May 1901, and Western News, 15 May 1901, as 
cited in Philip, "Journalistic View," 114. 

45. Minutes of the MSBH, 9 May 1901, in MSBH, First Biennial Report, 
9—10; Western News, 15 May 1901, and Daily Missoulian, 11 June 1901, as 
cited in Philip, "Journalistic View^," 11 4-1 5. 

46. Daily Missoulian, 11 June 1901, as cited in Philip, "JournaHstic View," 
115- 

47. Western News, 17 April 1901, as cited in Philip, "JournaHstic View," 
115- 

48. Western News, 22 May 1901, as cited in ibid. The physician was James 
William Howard. 

49. Edward Burrows, letter to the editor of the Western News, 5 June 1901, 
clipping in RML Scrapbook "1919-1931"; also cited in Philip, "Journalistic 
View," 115. 

50. Report of Louis B. Wilson and William M. Chowning in MSBH, First 
Biennial Report, 36. 

Chapter Three: The Beginning of Scientific Investigations 

1. Minutes of the meeting on 4 February 1902, of the MSBH in MSBH, 
First Biennial Report, 13; Northwest Tribune, 11 April 1902, as cited in Philip, 
"JournaHstic View" (see chap. 2, n. 10), 124. 

2. Western News, 30 April 1902, as cited in Philip, "Journalistic View," 
121. Two local physicians presented clinical papers on spotted fever at the 
meeting of the Montana Medical Association in Anaconda on 23 May 1902. 
George T. McCullough's paper "Spotted Fever" was published in the Medical 
Sentinel (see chap. 2, n. 32). Russell Gwinn's paper was not published in a 
medical periodical. 

3. Daily Missoulian, 2 May 1902, as cited in Philip, "Journalistic View," 
121. 

4. Esther Gaskins Price, Fighting Spotted Fever in the Rockies (Helena: 
Naegele Printing Co., 1948), 16-19, states that Strain suggested the significance 
of the tick to Longeway during a trip to the Bitterroot in 1901. No report of 
a 1 90 1 visit appears in contemporary newspapers, but several obituaries of 
Strain repeat the story and give 1901 as the date. See "Dr. Earle Strain, 
Discoverer of Relationship between Wood Ticks, Spotted Fever, Dies," "Dr. 
Earle Strain Dies in Great FaHs," and "Death Takes Expert on Spotted Fever," 
clippings dated 1953 in Scrapbook "1942- ," RML Scrapbooks. The MSBH, 
First Biennial Report, 25, records Strain's 1902 visit to the vaUey. Other 
documentation of the 1902 visit is in Daily Missoulian, 6 May 1902, as cited 
in Philip, "JournaHstic View," 121; Charles WardeH Stiles, "A Zoological 
Investigation into the Cause, Transmission, and Source of Rocky Mountain 
'Spotted Fever,' " U.S. Hygienic Laboratory Bulletin no. 20 (1905), 17. 



270 



Notes to Pages 24—^0 



5. Daily Missoulian, 3, 6, 8, 9, and 10 May, Western News, 7, 14, 21 May 
1902, as cited in Philip, "Journalistic View," 1 21-122. 

6. For biographical information on Wilson see Samuel F. Haines and Clark 
W. Nelson's sketch of him in the Dictionary of American Biography, 20 vols., 
6 supplements, (New York: Charles Scribner's Sons, 1932-80), suppl. 3 
(i973):83i-33 (hereafter cited as DAB). Wilson's papers, which are at the 
Mayo Clinic, unfortunately do not include manuscript materials relating to 
his spotted fever work. 

7. Frank F. Wesbrook, Louis B. Wilson, and O. McDaniel, "Varieties of 
Bacillus Diphtheria," Transactions of the Association of American Physicians 
15 (i90o):i98— 223. For biographical information on Wesbrook see H. E. 
Robertson's sketch of him, DAB 20 {19^6):}— 4. For biographical information 
on Mallory, see Shields Warren's sketch of him, ibid., suppl. 3 (i973):502- 
3- 

8. Biographical information on Chowning was kindly supplied by the Library 
and Information Management Section of the AMA. Because Chowning's li- 
cense was revoked in 1936 following his conviction for "the crime of abortion," 
JAMA did not pubHsh an obituary. 

9. Western News, 21 May 1902, as cited in Philip, "Journalistic View," 
122; Louis B. Wilson and William M. Chowning, "Studies in Pyroplasmosis 
Hominis ('Spotted Fever' or 'Tick Fever' of the Rocky Mountains)," Journal 
of Infectious Diseases 1 (i904):3i— 33; MSBH, First Biennial Report, 26—27. 

10. MSBH, First Biennial Report, 26; Wilson and Chowning, "Studies in 
Pyroplasmosis Hominis," 41-42. 

11. MSBH, First Biennial Report, 29; see also case records, ibid., 32-41. 

12. Wilbur Catlin, a local civil engineer and draftsman, prepared the dis- 
tribution maps for Wilson and Chowning. See Western News, 25 June 1902, 
as cited in Philip, "Journalistic View," 124. On the foci of spotted fever outside 
the Bitterroot, see Wilson and Chowning, "Studies in Pyroplasmosis Hominis," 
34. 

13. Percy M. Ashburn, "Piroplasmosis Hominis (?) — Spotted Fever of Mon- 
tana," Lancet-Clinic, n.s. 54 (1905)1481-94 (quotation from p. 492). 

14. MSBH, First Biennial Report, 42-44. 

15. Mortality figures computed by the author from Wilson and Chowning's 
tables, ibid., 32-41. Counts and computation by the author based on cases 
cited in Philip, "Journalistic View," 82-83, 86, 90—91, 95, 101-2, 107-8, 
116-17, 124-25. 

16. MSBH, First Biennial Report, 27; Wilson and Chowning, "Studies in 
Pyroplasmosis Hominis," 43-44. 

17. Walter Reed, Victor C. Vaughn, and Edward O. Shakespeare, Report 
on the Origin and Spread of Typhoid Fever in U.S. Military Camps during 
the Spanish War of 1898 (Washington, D.C.: Government Printing Office, 
1904); M. A. Veeder, "Flies as Spreaders of Disease in Camps," Medical 
Record, 17 September 1898, 429-30; William B. Bean, Walter Reed: A Bi- 
ography (Charlottesville: University Press of Virginia, 1982), 87-91; Edward 
F. Keuchel, "Chemicals and Meat: The Embalmed Beef Scandal of the Spanish- 
American War," Bull. Hist. Med. 48 (1974): 249-64. 

18. For surveys of scientific developments in parasitology, see William D. 
Foster, A History of Parasitology (Edinburgh: E. & S. Livingstone, 1965); 
Jean Theodorides, "Les Grandes Etapes de la parasitologie," Clio Medica i 
(1966): 129-45, 185-208. For a short survey of social and economic factors 



Notes to Pages 



271 



in the professionalization of parasitology, see Michael Worboys, "The Emer- 
gence and Early Development of Parasitology," in Kenneth S. Warren and 
John Z. Bowers, eds., Parasitology: A Global Perspective (New York: Springer- 
Verlag, 1983), 1-18. 

19. Patrick Manson, "On the Development of Filaria sanguinis hominis, 
and on the Mosquito Considered as a Nurse," Journal of the Linnean Society 
14 (i878):304-ii. This worm was later renamed Wucheria bancrofti. 

20. L. O. Howard, "A Fifty Year Sketch History of Medical Entomology 
and Its Relation to Public Health," in Mazyck P. Ravenel, ed., A Half Century 
of Public Health (New York: American PubHc Health Association, 1921), 413; 
H. Harold Scott, A History of Tropical Medicine, 1 vols. (London: Edward 
Arnold, 1939), 2:1086-90. 

21. Theobald Smith and F. L. Kilbourne, "Investigations into the Nature, 
Causation, and Prevention of Texas or Southern Cattle Fever," U.S. Department 
of Agriculture, Bureau of Animal Industry Bulletin no. i (1893); Tamara Miner 
Haygood, "Cows, Ticks, and Disease: A Medical Interpretation of the Southern 
Cattle Industry," /owm<3/ of Southern History 52 (i986):55i-64. 

22. Koch's postulates were articulated in his paper demonstrating the eti- 
ology of tuberculosis. He stated: "It was necessary to isolate the bacilli from 
the body, to grow them in pure culture until they were freed from any disease- 
product of the animal organism which might adhere to them; and, by ad- 
ministering the isolated bacilli to animals, to reproduce the same morbid 
condition which, as known, is obtained by inoculation with spontaneously 
developed tuberculous material." See Robert Koch, "Die Aetiologie der Tuber- 
culose," Berliner Klinische Wochenschrift 19 (1882): 221-30; hereafter cited 
as Berl. klin. Wchnschr. An English translation of this paper is in idem. The 
Aetiology of Tuberculosis, trans. Dr. and Mrs. Max Pinner (New York: Na- 
tional Tuberculosis Association, 1922) (quotation from p. 31). Lester S. King 
has pointed out that even for bacterial diseases, the postulates had to be 
understood as a method of elucidating a known disease process, not as a means 
of defining disease. See King, "Dr. Koch's Postulates," /. Hist. Med. Allied 
Sci. 7 (i952):350-6i. 

23. Sally Smith Hughes, The Virus: A History of the Concept (New York: 
Science History Publications, 1977), 12, 17—21. Evidence of the assumption 
that yellow fever was a protozoan disease may be seen in Herman B. Parker, 
George E. Beyer, and O. L. Pothier, "Report of Working Party No. 1, Yellow 
Fever Institute: A Study of the Etiology of Yellow Fever," U.S. Public Health 
and Marine Hospital Service Yellow Fever Institute Bulletin no. 13 (1903), 
esp. 28-3 2; Milton J. Rosenau, Herman B. Parker, Edward Francis, and George 
E. Beyer, "Report of Working Party No. 2, Yellow Fever Institute: Experimental 
Studies in Yellow Fever and Malaria at Vera Cruz, Mexico," in ibid. no. 14 
(1905); Milton J. Rosenau and Joseph Goldberger, "Report of Working Party 
No. 3, Yellow Fever Institute: Attempts to Grow the Yellow Fever Parasite; 
the Hereditary Transmission of the Yellow Fever Parasite in the Mosquito," 
in ibid. no. 15 (1906); Joseph Goldberger, "Yellow Fever: Etiology, Symptoms, 
and Diagnosis," in ibid. no. 16 (1907), 8-9. 

24. Hughes, The Virus, 61—73. 

25. Victoria A. Harden, "Rocky Mountain Spotted Fever Research and the 
Development of the Insect Vector Theory, 1900-19 30," Bull. Hist. Med. 59 
(i985):45i-52; George Henry Falkiner Nuttall, "On the Role of Insects, 
Arachnids, and Myriapods as Carriers in the Spread of Bacterial and Parasitic 



272 



Notes to Pages 32.-^6 



Diseases of Man and Animals: A Critical and Historical Study," /o^ws Hopkins 
Hospital Reports 8 (i899):43-49, 71-75. 

26. For examples of the association between ticks and blood poisoning, see 
Bitter Root Times, 12 June 1896, as cited in Philip, "Journalistic View," 86. 

27. Wilson and Chowning, "Studies in Pyroplasmosis Hominis," 44-45. 
See also L. B, Wilson and W M. Chowning, "The Hematozoon of the So- 
called 'Spotted Fever' of the Rocky Mountains," Northwest Lancet 22 
(i902):440-42. 

28. Western News, 11 June 1902, as cited in Philip, "Journalistic View," 
123. 

29. Wilson and Chowning, "Studies in Pyroplasmosis Hominis," 47-48. 

30. MSBH, First Biennial Report, 82. 

31. J. O. Cobb, "The So-called 'Spotted Fever' of the Rocky Mountains — 
A New Disease in the Bitter Root Valley, Mont.," Pub. Health Rep. 17 
(i902):i869. In 1902 the ground squirrel was known as Spermophilus colum- 
bianus. 

32. MSBH, First Biennial Report, 83. 

33. Charles Wardell Stiles, "Zoological Pitfalls for the Pathologist," Pro- 
ceedings of the New York Pathological Society, 1905, 16. 

34. Northwest Tribune, 4 July 1902, as cited in Philip, "Journalistic View," 
123. 

35. Sundry Civil Appropriations Act, 3 March 1901, 31 Stat. L. 1137. On 
the history of federal medical research policy, see Victoria A. Harden, Inventing 
the NIH: Federal Biomedical Research Policy, i88j—i^^y (Baltimore: Johns 
Hopkins University Press, 1986), chs. 1—2; Cobb, "The So-called 'Spotted 
Fever,' " 1868. 

36. For biographical information on Cobb see his personnel file. Record 
Group 090-78, Accession no. 0001, Agency Box no. OF, Records Center 
Location no. FU#i 34867 through FU#i 34992, box # 22, NARA, Saint 
Louis; Cobb, "The So-Called 'Spotted Fever,' " 1868, 1870; Wilson and 
Chowning, "The So-called 'Spotted Fever' of the Rocky Mountains: A Pre- 
liminary Report to the Montana State Board of Health," /AMA 39 (1902): 131- 
36. 

37. MSBH, First Biennial Report, 13. 

38. Ravalli Republican, 24 April 1903, and Daily Missoulian, 16 April 
1903, as cited in Philip, "Journahstic View," 130. 

39. For biographical information on Anderson, see Ralph C. Williams, The 
United States Public Health Service, 1798-19^0 (Washington, D.C.: Com- 
missioned Officers Association, 195 1), 251-52; Paul F. Clark, Pioneer Mi- 
crobiologists of America (Madison: University of Wisconsin Press, 1961), 211; 
Anderson's personnel file, Record Group 090-78, Accession no. 0001, Agency 
Box no. OF, Records Center Location no. FU# 134867 through FU#i34992, 
Box # 3, NARA, Saint Louis. 

40. John F. Anderson, "Spotted Fever (Tick Fever) of the Rocky Mountains: 
A New Disease," U.S. Hygienic Laboratory Bulletin no. 14 (1903): 7, 10, 21 
(quotation from p. 10); Wilson and Chowning, "Studies in Pyroplasmosis 
Hominis," 32; Daily Missoulian, 21 May 1903, as cited in Philip, "JournaHstic 
View," 130. 

41. See Anderson, "Spotted Fever." This report also appeared in MSBH, 
Second Biennial Report, 123-58; and in summary form with the same title. 



Notes to Pages 37-40 



273 



"Spotted Fever (Tick Fever) of the Rocky Mountains: A New Disease," in 
American Medicine 6 (1903): 506-8. 

42. Stiles, "Zoological Investigation," 25; see also Stiles's discussion of the 
infectivity of Firoplasma in idem, "Zoological Pitfalls," 18. 

43. Ashburn, "Piroplasmosis Hominis (?)," 492. 

44. Western News, 6 May 1903, as cited in Philip, "Journalistic View^," 
129. 

45. Western News, 20 April 1904, as cited in Philip, "Journalistic View," 
136. 

46. Stevensville Register, 18 May 1904, and Ravalli Republican, 29 April 
1904, as cited in Philip, "Journalistic View," 137. 

47. Northwest Tribune, 6 May 1904, as cited in Philip, "Journalistic View," 
137. 

48. Western News, 6 May 1903, as cited in Philip, "Journalistic View," 
129. 

49. Western News, 20 May 1903, and Ravalli Republican, 17 June 1904, 
as cited in Philip, "Journalistic View," 129, 138. 

50. Elsie McCormick, "Death in a Hard Shell," Saturday Evening Post, 15 
November 1941, 24ff. (quotation from p. 47); advertisement in the Daily 
Missoulian, 20 June 1902, as cited in Philip, "Journalistic View," 125. 

51. Stevensville Register, 15 June 1904, as cited in Philip, "Journalistic 
View," 138. For a survey of the history of quackery and patent medicines 
before the passage of the 1906 Pure Food and Drugs Act, see James Harvey 
Young, The Toadstool Millionaires: A Social History of Patent Medicines in 
America before Federal Regulation (Princeton, N.J.: Princeton University Press, 
1961); idem. Pure Pood: Securing the Federal Food and Drug Act of 1906 
(Princeton, NJ.: Princeton University Press, 1989). 

52. Anderson, "Spotted Fever," 40; MSBH, Second Biennial Report, 156; 
Anderson, summary version of "Spotted Fever," American Medicine 6 (1903): 
508. 

53. See, for example, an instance reported in the Daily Missoulian, 21 April 
and 24 May 1903, as cited in Philip, "Journalistic View," 132. 

54. MSBH, Second Biennial Report, 6—7. 

55. For biographical information on Tuttle, see his obituary in Montana 
Record Herald (Helena), 9 July 1942. 

56. During his first three months in office, Tuttle reinstated a three-week 
quarantine for measles, threatened county and local state health officers with 
lawsuits if they failed to report births, deaths, and infectious diseases, and 
initiated publication of the Montana Health Bulletin. See MSBH, Second 
Biennial Report, 8-13. 

57. Ibid., 9, 44-45. 

58. There are many biographical articles on Stiles, including James H. 
Cassedy's sketch of him, DAB, suppl. 3 (i903):737— 39; and an autobiograph- 
ical article, "Early History, in Part Esoteric, of the Hookworm (Uncinariasis) 
Campaign in Our Southern U.S.," Journal of Parasitology 25 (i939):283- 
308. For accounts of Stiles's work with hookworm, see Stiles, "Early History"; 
James H. Cassedy, "The 'Germ of Laziness' in the South, 1900— 191 5: Charles 
Wardell Stiles and the Progressive Paradox," Bull. Hist. Med. 45 (1971):! 59- 
69; John Ettling, The Germ of Laziness: Rockefeller Philanthropy and Public 
Policy in the New South (Cambridge, Mass.: Harvard University Press, 198 1). 



^74 



Notes to Pages 40-46 



59. Stiles, "Zoological Investigation," 10. 

60. Charles Wardell Stiles, "Insects as Disseminators of Disease," Virginia 
Medical Semi-Monthly 6 (i90i):53-58 (quotation from p. 54). Stiles's italics. 

61. Stiles, "Zoological Investigation," 11; PH-MHS, Annual Report, 1904, 
362. 

62. Stiles, "Zoological Pitfalls," 11-12. 

63. Stiles, "Zoological Investigation," 7, 19; PH-MHS, Annual Report^ 
1904, 362-63. 

64. Charles F. Craig, "The Relation of the So-called Piroplasma Hominis 
and Certain Degenerative Changes in the Erythrocytes," American Medicine 
8 (i904):ioi6. For biographical information on Craig, who from 19 18 to 
1920 served as curator of the Army Medical Museum, see Robert S. Henry, 
The Armed Forces Institute of Pathology: Its First Century, 1861-1961 (Wash- 
ington, D.C.: Office of the Surgeon General of the Army, 1964), 189; "Charles 
F. Craig," in American Men of Science^ 5th ed., ed. J. McKeen Cattell and 
Jacques Cattell (New York: Science Press, 1933), 239. In a personal com- 
munication to the author, 16 February 1988, Robert N. Philip suggested that 
Wilson and Chowning's observations could have been affected if their patients' 
blood were infected with Colorado tick fever virus, also present in the Bit- 
terroot, although unknown at that time. 

65. Stiles, "Zoological Investigation," 29-30. 

66. Ibid., 8, 49, 65. 

67. Ibid., 20. Ashburn likewise believed that if no protozoan organism were 
found in the blood, "the tick and gopher hypothesis would seem to die of 
inanition, as it was merely a hypothesis advanced to account for the protozoon 
infection." See Ashburn, "Piroplasmosis Hominis (?)," 491. The spelling of 
the Latin words protozoan and protozoon changes according to the word's 
grammatical use in the sentence. 

68. Stiles, "Zoological Investigation," 10. 

69. Ibid., 44; Ashburn, "Piroplasmosis Hominis (?)," 483-85. 

70. Stiles, "Zoological Investigation," 23. 

71. Ibid., 32, 35. 

72. PH-MHS, Annual Report, 1904, 363. Stiles's summary report also 
appeared in MSBH, Second Biennial Report, 160-62 (quotation from p. 162). 

73. Price, Fighting Spotted Fever, 34-36. 

74. Cassedy, " 'Germ of Laziness,' " 161; James H. Cassedy, "Applied 
Microscopy and American Pork Diplomacy: Charles Wardell Stiles in Ger- 
many, 1898-1899," Isis 62 (i97i):5-20. 

75. Stiles, "Zoological Pitfalls," 20. 

76. Stiles noted the lack of any such experiment, ibid., 15. 

77. Rankin's death was reported in the Daily Missoulian, 4 May 1904. His 
and other cases of spotted fever in 1904 are cited in Philip, "Journalistic View," 
137-38. 

78. Percy M. Ashburn, "A Suggestion as to the Treatment of the 'Spotted 
Fever' of Montana," Lancet-Clinic, n.s. 54 (i905):579-84 (quotation from 
P- 579)- 

79. On hydrotherapy see Marshall Scott Legan, "Hydropathy in America: 
A Nineteenth Century Panacea," Bull. Hist. Med. 45 (1971): 267-80; John 
Harvey Kellogg, Rational Hydrotherapy: A Manual of the Physiological and 
Therapeutic Effects of Hydriatic Procedures, and the Technique of Their Ap- 



Notes to Pages 46-^0 



^75 



plication in the Treatment of Disease, id ed. (Philadelphia: F. A. Davis Co., 
1903); Simon Baruch, Principles and Practice of Hydrotherapy (London: Bail- 
liere, Tindall & Co., 1900). Osier's recommendation is in Principles and 
Practice of Medicine, 43. 

80. Ashburn, "Suggestion as to the Treatment," 583, 581; Robert N. Philip, 
personal communication to the author, 16 February 1988. 

81. "Spotted Fever," /AMA 44 (i905):i686. 

Chapter Four: Dr. Ricketts's Discoveries 

1. See, for example, references to such changes in Western News, 3 July 
1907, 1 July 1908, and 27 July and 9 September 1910, and Ravalli Republican, 
26 March 1909, all cited in Philip, "Journalistic View^" (see chap. 2, n. 10), 
158-59, 165, 176, 180. 

2. MSBH, Second Biennial Report, 66, 58, 67-68. 

3. Robert William Hadlow, "The Big Ditch and the Mcintosh Red: Early 
Boosterism in Montana's Bitter Root Valley," Pacific Northwest Forum 8 (Fall 
i983):2-i3; Western News, 30 October 1907, as cited in Philip, "Journalistic 
View," 157. 

4. Philip identified the following cases and deaths from spotted fever in this 
period — 1904: 14 cases, 9 deaths; 1905: 10 cases, 8 deaths; 1906: 14 cases, 
II deaths; 1907, 6 cases, 6 deaths; 1908: 10 cases, 4 deaths; 1909, 10 cases, 
8 deaths; 19 10: 8 cases, 8 deaths. See "Journalistic View," 137-38, 146-47, 
154-55, i^ij 167-68, 176, 180. His figures for 1909 include four fatal cases 
in Northern Pacific Railroad workers that were never reported in the press. 
On the creation of the Montana Bureau of Vital Statistics and registration of 
births and deaths, see Daily Missoulian, 30 May 1907, as cited in Philip, 
"JournaHstic View," 156. 

5. Wyman to the Secretary of the Treasury, 19 April 1905, file 1266, box 
119, Central File, 1 897-1923, PHS Records. For biographical information on 
Francis see American Men of Science, 5th ed. (see chap. 3, n. 64), 378; WilHams, 
United States Public Health Service (see chap. 3, n. 39), 190—92; and Clark, 
Pioneer Microbiologists (see chap. 3, n. 39), 62, 296—97. 

6. Daily Missoulian, 11 June 1905, as cited in Philip, "Journalistic View," 
146. Francis's investigation was mentioned in the 1905 and 1906 annual 
reports of the Service, but no report of substance was ever published. See PH- 
MHS, Annual Report, 1905, 211; and 1906, 219. 

7. Stiles, "Zoological Pitfalls" (see chap. 3, n. 33). The observer was S. Burt 
Wolbach, whose comment was pubHshed in "Studies on Rocky Mountain 
Spotted Yevev,'' Journal of Medical Research 41 (i9i9):i-i97 (quotation from 
p. 9). 

8. Chowning to Ricketts, 15 March 1906; and Ricketts to Chowning, 17 
March 1905 (letter misdated; should be 1906), box 8, folder 9, Ricketts Papers. 

9. Chowning to Ricketts, 15 March 1906, box 8, folder 9, Ricketts Papers; 
Lucien P. McCalla, "Direct Transmission from Man to Man of the Rocky 
Mountain Spotted (Tick) Fever," Medical Sentinel 16 (i9o8):87-88. For bi- 
ographical information on McCalla see Hammarsten, "Contributions of Idaho 
Physicians" (see chap. 2, n. 35), 31-33. 

10. Howard Taylor Ricketts, Infection, Immunity, and Serum Therapy (Chi- 
cago: American Medical Association, 1906). For biographical information on 



276 



Notes to Pages 51-54 



Ricketts, see Pierce C. Mullen's sketch of him in Charles Coulston Gillispie, 
ed., Dictionary of Scientific Biography, 16 vols. (New York: Charles Scribner's 
Sons, 1970-80), II (i975):442-43; William K. Beatty and Virginia L. Beatty, 
"Howard Taylor Ricketts— Imaginative Investigator," Proceedings of the In- 
stitute of Medicine of Chicago 34 ( 198 1) 146-48; Ludvig Hektoen's memorial 
address on Ricketts, in Howard T. Ricketts, Contributions to Medical Science 
by Howard Taylor Ricketts, iSjo-i^io (Chicago: University of Chicago Press, 
1911), 3-7; H. Gideon Wells's sketch of him, DAB (see chap. 3, n. 6), suppl. 
I (1944), 628—29; Clark, Pioneer Microbiologists, 285—91; obituary, /AMA 
54 (i9io):i640. No book-length biography of Ricketts has yet been written. 
On Ricketts's study with Henry B. Ward, see Edwin F. Hirsch, "The Insect 
Vector as Transmitter of Disease," Proceedings of the Institute of Medicine 
of Chicago 27 (i969):294. On medical education during this period, see the 
classic report of Abraham Flexner, Medical Education in the United States 
and Canada (New York: Carnegie Foundation, 19 10). An excellent recent 
study is Kenneth M. Ludmerer, Learning to Heal: The Development of Amer- 
ican Medical Education (New York: Basic Books, 1985). 

11. Spottswood to Ricketts, 10 April 1906; and Ricketts to Tuttle, 29 June 
1906, box 8, folder 9, Ricketts Papers; Ricketts's report in MSBH, Third 
Biennial Report, 22—23; William M. Chowning, "Rocky Mountain Spotted 
Fever: Preliminary Reports," Journal of the Minnesota State Medical Asso- 
ciation and the Northwest Lancet 27 (1907) :ioi. 

12. Williams, United States Public Health Service, 261-62; "Science Takes 
Doctors' Lives: Voluntarily They Assume Risks in Studying Various Forms of 
Disease," Boston Herald, 17 July 1910, clipping in "1909-1911 Scrapbook," 
box 3, U.S. Public Health Service Scrapbooks, Manuscripts Collection, NLM; 
PH-MHS, Annual Report, 1905, 216—17. Some of the hookworm control 
methods developed by King, Ashford, and Gutierrez were later adapted by 
the Rockefeller Hookworm Commission for use in the southern United States. 

13. There are virtually no primary records available regarding King's work 
on spotted fever. His comments on Ricketts were made to a newspaper reporter 
shortly after Ricketts died of typhus. See "Science Takes Doctors' Lives," cited 
above. 

14. My discussion of these methods follows Paul Clark's summary in Pioneer 
Microbiologists, 96—98. 

15. Ricketts to Tuttle, 29 June 1906, box 8, folder 9, Ricketts Papers; MSBH, 
Third Biennial Report, 23-24, 26; Howard Taylor Ricketts, "The Study of 
'Rocky Mountain Spotted Fever' (Tick Fever?) by Means of Animal Inocu- 
lations," JAMA 47 (i9o6):33. Rabbits were later proven to be susceptible to 
spotted fever, but they never displayed so marked a reaction as did guinea 
pigs. See Liborio Gomez, "Rocky Mountain Spotted Fever in the Rabbit," 
/. Inf. Dis. 6 (i909):383-86. 

16. Daily Missoulian, 15 and 24 May 1906, as cited in Philip, "JournaHstic 
View," 153; MSBH, Third Biennial Report, 34. 

17. MSBH, Third Biennial Report, 24-28; Ricketts to Tuttle, 29 June 1906, 
box 8, folder 9, Ricketts Papers; Ricketts, "Study of 'Rocky Mountain Spotted 
Fever' (Tick Fever?) by means of Animal Inoculations," 33—36, 

18. A newspaper account stated that "it is feared" Etta Bradley "cannot 
recover." She did recover, however, and lived in the Bitterroot until her death 
in 1980. See Daily Missoulian, 13 June 1906, as cited in Philip, "Journalistic 



Notes to Pages 55-57 



^77 



View," 155; William L. Jellison, "Jellison Recalls Bradley Contribution," Ra- 
valli Republic^ 19 November 1980, 9. Robert N. Philip, in a personal com- 
munication to the author, i6 February 1988, noted that in 1962, fifty-six 
years after her illness, Etta Bradley McKinney's blood still produced a com- 
plement fixation titer of 1:8. 

19. Ricketts to Tuttle, 29 June 1906, box 8, folder 9, Ricketts Papers; MSBH, 
Third Biennial Report, is-z6; Ricketts, "Study of 'Rocky Mountain Spotted 
Fever' (Tick Fever?) by Means of Animal Inoculations," 34. 

20. R. R. Parker, "Certain Phases of the Problem of Rocky Mountain Spotted 
Fever: A Summary of Present Information," Archives of Pathology 15 
(i933):398-429 (first demonstration of tick transmission of human disease 
in United States noted on p. 400) ; Walter W. King, "Experimental Transmission 
of Rocky Mountain Spotted Fever by Means of the Tick," Pub. Health Rep. 
21 (1906) 1863-64; Ricketts, "The Transmission of Rocky Mountain Spotted 
Fever by the Bite of the Wood Tick {Dermacentor occidentalis),'' JAMA 47 
(i906):358. 

21. Ricketts, "Transmission of Rocky Mountain Spotted Fever," 358. The 
question of scientific priority has alv^ays been a sensitive issue. Rolla E. Dyer, 
himself a distinguished rickettsial investigator and director of the NIH, inserted 
a handwritten note on King's article — in the copy now held in the NIH Hbrary — 
to reemphasize King's priority to later readers. Dated 12 May 193 1, it reads: 
"W. W. King returned to Hy. Lab. from Montana June 29, 1906. Ricketts fed 
his first ticks on an infected pig June 19, 1906. Placed them on non-infected 
pig on June 23, 1906. This pig developed fever June 27, 1906. Therefore the 
experiments of King and Ricketts must have run concurrently. King certainly 
started his experiment before Ricketts's experiment was positive. King's pub- 
lication precedes Ricketts. Therefore, the priority belongs to King— although 
Ricketts may have first suggested the experiment." 

22. Ricketts to Tuttle, 25 June 1906, box 8, folder 9, Ricketts Papers. 

23. For example, in 1908, Ricketts refused the request of a Dr. Smith for 
ticks infected with spotted fever. "It doesn't sound generous," he wrote, but 
explained that he had reached this position "as a result of some unpleasant 
experiences which I want to avoid in the future." See Ricketts to Maria B. 
Maver, 18 June 1908, box 8, folder 11, Ricketts Papers. Walter W. King also 
noted that Ricketts was "a little given to reticence about results he had obtained 
until ready to make them pubhc." See "Science Takes Doctors' Lives." 

24. "The Transmission of Rocky Mountain Spotted Fever by Ticks," JAMA 
47 (i9o6):366. 

25. MSBH, Third Biennial Report, 34-35; "State Association Meeting," 
JAMA 46 (1906): 1704. 

26. "The Value of the People of Montana," in MSBH, Third Biennial Report, 
12-20 (quotations from pp. 18-20); "Investigation of the Cause and Means 
of Prevention of Rocky Mountain Spotted Fever Carried on During 1907 and 
1908 by Dr. Howard Taylor Ricketts of the University of Chicago," in MSBH, 
Fourth Biennial Report, 78. 

27. Ricketts to Tuttle, 29 June 1906, box 8, folder 9, Ricketts Papers; MSBH, 
Third Biennial Report, 29. 

28. See newspaper requests for citizens to collect ticks for both King and 
Ricketts in Western News, 29 November and 19 December 1906, and Stev- 
ensville Register, 8 August and 26 December 1906, as cited in Philip, "Jour- 
nahstic View," 153-54. 



278 



Notes to Pages S7~59 



29. T. W. Goodspeed to Ricketts, 21 March 1907, box 4, folder 15, Ricketts 
Papers. Goodspeed was secretary of the University of Chicago Board of Trus- 
tees. In a personal communication to the author, 16 February 1988, Robert 
N. Philip commented on the four nymphal ticks "taken from horses" that 
Ricketts used for his early experiments: "Very likely these were D. albipictus 
(the elk winter tick), which at that time had not yet been distinguished from 
'D. occidentalis' [actually D. andersoni]. D. albipictus is a one-host tick, active 
in the winter time. D. andersoni nymphs are seldom active in the winter, and 
seldom found on large animals. Because it is strictly a one-host tick, D. al- 
bipictus was never considered to be important in the transmission cycle and 
hence, to my knowledge, was never tested for its experimental transmission 
potential by Ralph R. Parker. My father [Cornelius B. Philip] raised this 
question some years ago." See C. B. Philip and G. M. Kohls, "Elk, Winter 
Ticks, and Rocky Mountain Spotted Fever: A Query," Pub. Health Rep. 66 
(i952):i672-75. 

30. Ricketts to Hektoen, 4 June 1907, box 8, folder 10, Ricketts papers; 
Howard Taylor Ricketts, "Observations on the Virus and Means of Trans- 
mission of Rocky Mountain Spotted Fever," /. Inf. Dis. 4 (1907): 141-53. 

31. Ricketts to Tuttle, 19 April 1907, box 8, folder 10, Ricketts Papers; 
Turtle to Ricketts, 3 May 1907, in Howard Taylor Ricketts, Scrapbook, 39, 
prepared by his family and deposited in selected libraries. The NLM has a 
copy. Holden's death on 22 April was reported in the Western News., 23 April 
1907, as cited in Philip, "Journalistic View," 161. 

32. William M. Chowning, "Studies in Rocky Mountain Spotted Fever," 
/. Minn. Med. Assn. 6c Northwest Lancet 28 (i9o8):45-49. Chowning in- 
cluded eighteen microphotographs from case studies in this paper, but because 
of the diversity of the organisms, he did not claim that any particular one 
caused spotted fever. 

33. Ricketts to [Hektoen], n.d., box 8, folder 10, Ricketts Papers. The first 
page of this letter is missing, but from the context it is clearly addressed to 
Hektoen. 

34. Ricketts to Hektoen, 4 June 1907, box 8, folder 10, Ricketts Papers. 

35. King's detachment from the Hygienic Laboratory and detail to San 
Francisco are noted in the Hygienic Laboratory Register, 30 July and 22 August 
1907, U.S. Hygienic Laboratory Registers, 1901—23, Manuscripts Collection, 
NLM (hereafter cited as Hygienic Laboratory Registers, NLM); his later po- 
sitions are noted in "Science Takes Doctors' Lives"; PH-MHS, Annual Report, 
1911, 272. 

36. Howard Taylor Ricketts, "A Micro-Organism Which Apparently Has 
a Specific Relationship to Rocky Mountain Spotted Fever: A Preliminary Re- 
port," JAMA 52 (1909): 3 79— 80. Ricketts also discussed these findings in the 
Wesley M. Carpenter Lecture at the New York Academy of Medicine. See 
idem, "Some Aspects of Rocky Mountain Spotted Fever as Shown by Recent 
Investigations," in idem, Contributions to Medical Science, 373-408. 

37. Howard Taylor Ricketts, "Spotted Fever Report No. i: General Report 
of an Investigation of Rocky Mountain Spotted Fever, Carried on during 1906 
and 1907," in MSBH, Fourth Biennial Report, 109; idem, "A Summary of 
Investigations of the Nature and Means of Transmission of Rocky Mountain 
Spotted Fever," Transactions of the Chicago Pathological Society 7 ( 1907): 73- 
82. 



Notes to Pages 

I 



279 



38. Ricketts to Turtle, 24 June 1909, folder i, "Rocky Mounrain Sporred 
Fever, 1908-1911," box i, "General Correspondence," MSBH Records. See 
also Ricketts, "The Role of the Wood-tick {Dermacentor occidentalis) in Rocky 
Mountain Spotted Fever, and the Susceptibility of Local Animals to This 
Disease: A Preliminary Report," ]AMA 49 [t^oj):z^—zj\ idem, "Further 
Experiments with the Wood-Tick in Relation to Rocky Mountain Spotted 
Fever," /AMA 49 (1907): 1278-81. 

39. Maria B. Maver, "Transmission of Spotted Fever by Other Than Mon- 
tana and Idaho Ticks," /. Inf. Dis. 8 (191 1)1322-26; idem, "Transmission of 
Spotted Fever by the Tick in Nature," ibid., 327-29. See also correspondence 
about these experiments in box 8, folder 12, Ricketts Papers. The common 
dog tick is known as Dermacentor variabilis (Say), the "lone star" tick as 
Amblyomma americanum (Linnaeus), and the Utah rabbit tick as Dermacentor 
parumapertus. 

40. Ricketts, "Spotted Fever Report No. i," 99-100. 

41. Ibid., 100-105. 

42. Ibid., 120; Ricketts to Tuttle, 23 November 1908, folder i, "Rocky 
Mountain Spotted Fever, 1908-19 11," box i, "General Correspondence," 
MSBH Records. 

43. Ricketts, "Spotted Fever Report No. i," 121-24. 

44. Ricketts to Tuttle, 8 January 1908; and Morgan to Ricketts, n.d. but 
late January 1908, from context, folder i, "Rocky Mountain Spotted Fever, 
1908-19 1 1," box I, "General Correspondence," MSBH Records; Ricketts, 
"Spotted Fever Report No. i," 124. 

45. Ricketts, "Spotted Fever Report No. i," 129-30; Ricketts to Tuttle, 19 
January 1908, folder i, "Rocky Mountain Spotted Fever, 1908— 191 1," box 
I, "General Correspondence," MSBH Records. Montana State College is now 
called Montana State University. 

46. Ricketts to Tuttle, 14 January 1908, folder i, "Rocky Mountain Spotted 
Fever, 1908-1911," box i, "General Correspondence," MSBH Records, 

47. Ricketts, "Spotted Fever Report No. i," 126. 

48. Ibid., 126-27. 

49. Quotation from ibid., 127; Josiah J. Moore, "Time Relationships of 
the Wood-Tick in the Transmission of Rocky Mountain Spotted Fever," /. Inf. 
Dis. 8 (i9ii):339-47. 

50. Western News, 19 June 1907, as cited in Philip, "Journalistic View," 
161; "Investors Flock to the Bitter Root Valley: Exhibition Takes Chicago by 
Storm!" Western News, 13 November 1907, and, on cherries. Western News, 
5 August 1908, both cited in Philip, "Journalistic View," 157, 164; Tuttle to 
Ricketts, 23 October 1909; and Ricketts to Tuttle, 9 November 1909, folder 
I, "Rocky Mountain Spotted Fever, 1908-1911," box i, "General Corre- 
spondence," MSBH Records. 

51. Ricketts to Hektoen, 4 June 1907, box 8, folder 10, Ricketts Papers. 
For a more complete discussion of these techniques, see George Clark and 
Frederick H. Kasten, History of Staining, 3d ed. (Baltimore: Williams & 
Wilkins, 1983), esp. 1 13-17. For a complete statement of Koch's postulates, 
see chap. 3, n. 22. 

52. W. A. Hooker, "A Review of the Present Knowledge of the Role of 
Ticks in the Transmission of Disease," Journal of Economic Entomology 1 
(i9o8):65-76, esp. charts on pp. 68, 69, 74; Rennie W. Doane, Insects and 



zSo 



Notes to Pages 64-68 



Disease: A Popular Account of the Way in Which Insects May Spread or Cause 
Some of Our Common Diseases (New York: Henry Holt, 1910), 32. 

5 3 . Ricketts, "A Micro-Organism," 3 79, 3 80. In this original article, Ricketts 
gave the dilutions as "up to i to 160." This was in error; the actual dilutions 
were up to i to 3 20. See Ricketts, letter of correction to the editor, JAMA 5 2 
(1909): 491. 

54. Ricketts, "Some Aspects of Rocky Mountain Spotted Fever as Shown 
by Recent Investigations," 397-98. 

55. Idem, "A Micro-Organism," 380. 

56. Ricketts to Tuttle, 25 January 1909, folder i, "Rocky Mountain Spotted 
Fever, 1908-19 11," box i, "General Correspondence," MSBH Records; Novy 
to Ricketts, 6 April 1909; and Chowning to Ricketts, 13 July 1909, box 8, 
folder 12, Ricketts Papers. 

57. Ricketts to Tuttle, 17 March 1909; and Ricketts to Tuttle, 24 June 
1909, folder I, "Rocky Mountain Spotted Fever, 1908-1911," box i, "General 
Correspondence," MSBH Records; McCampbell to Ricketts, 22 November 
1909, box 8, folder 12, Ricketts Papers. 

58. Ricketts to Hektoen, 4 June 1907, box 8, folder 10, Ricketts Papers; 
Howard Taylor Ricketts and Liborio Gomez, "Studies on Immunity in Rocky 
Mountain Spotted Fever: First Communication," /. Inf. Dis. 5 (i9o8):22i- 
44 (quotations from p. 235). 

59. Ricketts and Gomez, "Studies on Immunity," 224, 236. 

60. Ibid., 228—30, 236—42. 

61. Ricketts to Tuttle, 17 March 1909; and Ricketts to Tuttle, 24 June 
1909, folder I, "Rocky Mountain Spotted Fever, 1908-1911," box i, "General 
Correspondence," MSBH Records. 

62. McCampbell to Ricketts, 8 August 1909; Ricketts to Hektoen, 23 
December 1909; and Ricketts to S. A. Matthews, 8 October 1909, box 8, 
folder 12, Ricketts Papers. 

63. Ricketts to Hektoen, 4 June 1907, box 8, folder 10, Ricketts Papers. 

64. Ricketts and Gomez, "Studies on Immunity," 230—32; Howard Taylor 
Ricketts, "Spotted Fever Report No. 2: A Report of Investigations Carried on 
during the Winter of 1907—8 and the Spring and Summer of 1908," in MSBH, 
Fourth Biennial Report, 138-42; Ricketts to Tuttle, 21 March 1908, folder 
I, "Rocky Mountain Spotted Fever, 1908-19 11," box i, "General Corre- 
spondence," MSBH Records. 

65. These cases are discussed in Ricketts, "Spotted Fever Report No. 2," 
144—49 (quotation from p. 146). 

66. All three recovered cases are identifiable in local press accounts. One 
paper attributed to the serum the recovery of a case that Ricketts himself never 
recorded. For all these cases see Philip, "Journalistic View," 167—68. 

67. Ricketts to Tuttle, 29 March 1909; and Ricketts to Tuttle, 24 June 
1909, folder I, "Rocky Mountain Spotted Fever, 1908-191 1," box i, "General 
Correspondence," MSBH Records. The serum sent in 1909 reportedly saved 
the life of Mrs. Harry H. Townsend, whose grateful husband wrote a letter 
of appreciation to their perceived benefactor. See Stevensville Register., 17 June 
1909, as cited in Philip, "Journalistic View," 176; Harry H. Townsend to 
Ricketts, 31 March 1910, box 8, folder 13, Ricketts Papers. 

68. Tuttle to Ricketts, 25 February 1908, folder i, "Rocky Mountain Spotted 
Fever, 1908-1911," box i, "General Correspondence," MSBH Records; 



Notes to Pages 68-yi 281 

MSBH Minutes, special session, 19 February 1908; Ricketts to Tuttle, 22 
October 1908; and [Ricketts and Tuttle], unsigned letter, to E. E. Maxey, 24 
October 1908, folder i, "Rocky Mountain Spotted Fever, 1908-1911," box 
I, "General Correspondence," MSBH Records. 

69. Tuttle to Ricketts, 5 March 1909; and Ricketts to Tuttle, 17 March 
1909, folder I, "Rocky Mountain Spotted Fever, 1908-1911," box i, "General 
Correspondence," MSBH Records. The bill passed the legislature on 4 March. 

70. MSBH Minutes, i April 1909; Tuttle to Cooley, 22 March 1909, folder 
I, "Rocky Mountain Spotted Fever, 1908-1911," box 1, "General Corre- 
spondence," MSBH Records. 

71. Romney to Tuttle, 25 April 1909; President, Montana Medical Asso- 
ciation, to Board of Education, 4 June 1909; and Ricketts to Tuttle, 24 June 
1909, folder I, "Rocky Mountain Spotted Fever, 1908-1911," box i, "General 
Correspondence," MSBH Records; Daily Missoulian, 14 May 1909, as cited 
in Philip, "JournaHstic Vievs^," 176. 

72. MSBH Minutes, i April 1909. See also correspondence in box 8, folder 
12, Ricketts Papers, regarding Ricketts's attempt to discuss this with the state 
board of examiners when the members of that body went to Chicago in late 
April 1909. 

73. See correspondence in box 4, folder 15, Ricketts Papers, about Ricketts's 
offers of positions. Ricketts received the gold medal for an exhibit on spotted 
fever research prepared by his assistant Maria B. Maver. See Ricketts to Maver, 
18 June 1908, box 8, folder 11, Ricketts Papers. 

74. Preliminary negotiations and financial arrangements for the typhus in- 
vestigations are documented in box 8, folder 12, and box 4, folder 15, Ricketts 
Papers; quotation from Ricketts to H. G. Wells, 12 February 19 10, box 8, 
folder 13, Ricketts Papers. On Ricketts's decision to go to Mexico, see also 
Russell M. Wilder, "The Rickettsial Diseases: Discovery and Conquest," Arch. 
Pathol. 49 (i95o):479-89. 

75. Charles Nicolle, C. Comte, and E. Conseil, "Transmission experimentale 
du typhus exanthematique par le pou du corps," Comptes Rendus de V Aca- 
demic des Sciences 149 (i909):486-89 (hereafter cited as Compt. Rend. Acad, 
d. Sc.); Wilder, "Rickettsial Diseases," 483-84; John F. Anderson and Joseph 
Goldberger, "On the Relation of Rocky Mountain Spotted Fever to the Typhus 
Fever of Mexico: A Preliminary Note," Pub. Health Rep. 24 (i909):i86i- 
62; Goldberger to Ricketts, 8 March 19 10, Ricketts, Scrapbook, 109; Howard 
Taylor Ricketts and Russell M. Wilder, "The Etiology of the Typhus Fever 
(Tabardillo) of Mexico City: A Further Preliminary Report," JAMA 54 
(1910): 1373-75. The entire series of Ricketts's and Wilder's papers on typhus 
are in Ricketts, Contributions to Medical Science, 451-500. 

76. Ricketts to Tuttle, 13 February 19 10; Ricketts to Tuttle, 12 March 19 10; 
Tuttle to Ricketts, 18 March 19 10; and Ricketts to Moore, 14 April 19 10, 
box 8, folder 13, Ricketts Papers. 

77. Ricketts to Moore, 14 April 1910; Moore to Ricketts, 13 April 1910; 
and Ricketts to H. G. Wells, 12 February 19 10, box 8, folder 13, Ricketts 
Papers. 

78. Wilder to Tuttle, 25 April 1910, folder i, "Rocky Mountain Spotted 
Fever, 1908-1911," box i, "General Correspondence," MSBH Records. See 
references to Ricketts's illness in box 8, folder 12, Ricketts Papers. Daily 
Missoulian, 5 May 19 10, as cited in Philip, "Journalistic View," 179. 



282 



Notes to Pages 71-7S 



79. Turtle to Moore, telegram, 4 May 19 10; and Wilder to Tuttle, 25 April 
1910, folder I, "Rocky Mountain Spotted Fever, 1908-1911," box i, "General 
Correspondence," MSBH Records; Ricketts to Judson, 23 April 1909, box 4, 
folder 15, Ricketts Papers. 

80. R G. Heinemann and Josiah J. Moore, for example, attempted to develop 
a more concentrated form of Ricketts's antiserum. The few human trials of 
its efficacy, however, were inconclusive. See Heinemann and Moore, "The 
Production and Concentration of a Serum for Rocky Mountain Spotted Fever: 
Preliminary Note," JAMA 57 (191 1): 198; idem, "Experimental Therapy of 
Rocky Mountain Spotted Fever: The Preventive and Curative Action of a 
Serum for Spotted Fever, and the Inefficiency of Sodium Cacodylate as a 
Curative Agent for This Disease in Guinea Pigs," /. Inf. Dis. 10 ( 19 12): 294- 
304. Other work by Ricketts's students and colleagues, published in Ricketts, 
Contributions to Medical Science, will be discussed and cited in later chapters. 

81. See correspondence regarding this in box 8, folder 13, Ricketts Papers. 

Chapter Five: Tick Eradication Efforts, ipii-i^zo 

1. Cornelius B. Philip and Lloyd E. Rozeboom, "Medico-Veterinary En- 
tomology: A Generation of Progress," in Ray F. Smith, Thomas E. Mittler, 
and Carroll N. Smith, eds.. History of Entomology (Palo Alto, Calif.: Annual 
Reviews, 1973), 333; R. Hoeppli, Parasites and Parasitic Infections in Early 
Medicine and Science (Singapore: University of Malaya Press, 1959), 187- 
88. 

2. Taxonomic systematics are discussed in most textbooks of zoology. My 
discussion follows that in William B. Herms, Medical Entomology: With 
Special Reference to the Health and Well-Being of Man and Animals (New 
York: Macmillan, 1939), 29-31, 422-23; and Wolbach's review of the spotted 
fever tick in his "Studies on Rocky Mountain Spotted Fever" (see chap. 4, n. 
7), 46-48. The word Dermacentor is derived from the Greek dermis., "skin," 
and kentor, "stinger," "pricker," or "goader." 

3. Report of Louis B. Wilson and William M. Chowning in MSBH, First 
Biennial Report, 27. 

4. Wilson and Chowning, "Studies in Pyroplasmosis Hominis" (see chap. 
3, n. 9), 51-52. 

5. Stiles, "Zoological Investigation" (see chap. 3, n. 4), 7; King, "Experi- 
mental Transmission" (see chap. 4, n. 20), 863; Ricketts, "Role of the Wood- 
Tick" (see chap. 4, n. 38), 24. 

6. Nathan Banks, "A Revision of the Ixodoidea, or Ticks, of the United 
States," Technical Services, Bureau of Entomology, U.S. Department of Ag- 
riculture Bulletin no. 15 (1908). The species name venustus means "lovely," 
"charming," or "beautiful." 

7. Charles Wardell Stiles, "The Common Tick {Dermacentor andersoni) of 
the Bitter Root Valley," Pub. Health Rep. 23 (i9o8):949; idem, "The Tax- 
onomic Value of the Microscopic Structure of the Stigmal Plates in the Tick 
Genus Dermacentor," U.S. Hygienic Laboratory Bulletin no. 62 (August 19 10), 
72 pp. and 43 plates; idem, "The Correct Name of the Rocky Mountain 
Spotted Fever Tick," ]AMA 55 (19 10): 1909-10; Nathan Banks, letter to the 
editor, JAMA 55 (1910): 1574-75. 

8. See, for example, MSBE, First Biennial Report, 12, 28. 



Notes to Pages 75-77 



283 



9. "Opinion 78 : Case of Dermacentor andersoni vs. Dermacentor venustus," 
in "Opinions Rendered by the International Commission on Zoological No- 
menclature: Opinions 78 to 81," Smithsonian Miscellaneous Collections 73, 
no. 2 (i924):i-i4 (quotation from pp. 13-14). The effect of this ruling, 
however, made D. venustus a vaHd "senior synonym" for D. andersoni if the 
names were applied to a single species. In 1976 an RML entomologist, James 
E. Keirans, with the support of many of his colleagues, successfully applied 
to the International Commission on Zoological Nomenclature to have the 
name D. venustus suppressed entirely, so that the name D. andersoni alone 
is now the official name for the Rocky Mountain wood tick. See James E. 
Keirans, "Dermacentor venustus Marx MS. in Neumann, 1897: Proposed 
Suppression under the Plenary Powers so as to Conserve Dermacentor an- 
dersoni Stiles, 1908 (Acarina: Ixodidae). Z.N.(S.) 260," Bulletin of Zoological 
Nomenclature 32 (i976):26i-64. I am grateful to Dr. Keirans for providing 
me with a copy of this paper. 

10. As late as 1928, for example, L. O. Howard, chief of the U.S. Bureau 
of Entomology, told delegates to an international congress of entomologists 
that zoologists, because of their conservatism, had consistently "slighted" 
entomology. See "Age of Insects, Not Man, Says Dr. L. O. Howard Opening 
Entomology Congress Here,'" Journal-News (Ithaca, N.Y.), 13 August 1928, 
clipping in RML Scrapbook "1919-1931." 

11. On early entomological research see Gustavus A. Weber, The Bureau 
of Entomology: Its History, Activities, and Organization, Institute for Gov- 
ernment Research, Service Monographs of the United States Government no. 
60 (Washington, D.C.: Brookings Institution, 1930), 1-13. On insect threats 
in 1876 see James Harvey Young, "Harper's Weekly on Health in America, 
1876,"/. Hist. Med. Allied Sci. 41 (i986):i56-74, esp. 162. 

12. Robert H. Wiebe, The Search for Order, 1877-1910 (New York: Hill 
& Wang, 1967); William B. Herms, "Medical Entomology, Its Scope and 
Methods,"/. Econ. Entomol. 2 (i909):265-68. 

13. It has been argued, for example, that veterinarian Fred L. Kilbourne 
was slighted in the allocation of credit for the Texas cattle fever tick trans- 
mission experiments because his physician-supervisor, Theobald Smith, 
claimed first-author privilege on their classic report. See J. F. Smithcors, "Dis- 
covery of the Arthropod Vector of Disease," Modern Veterinary Practice 62 
(i98i):37i-74. 

14. Turtle to Wyman, 2 March 191 1; and Thomas B. McClintic, "Mem- 
orandum Relative to Investigations of Rocky Mountain Spotted Fever," 5 July 
1911, file 1266, box 119, Central File, 1897-1923, PHS Records; PH-MHS, 
Annual Report, 191 1, 40—42. 

15. Biographical information on McClintic is taken from his personnel file, 
Record Group 090-78, Accession no. 0001, Agency Box no. OF, Records 
Center Location no. FU# 134867 through FU# 134992, box # 77, NARA, 
Saint Louis (hereafter cited as McClintic personnel file, NARA, Saint Louis); 
Blue to F. M. Wilmot, 25 November 19 12, in ibid.; McClintic, "Memorandum 
Relative to Investigations." 

16. McClintic to Wyman, 5 July 191 1, file 1266, box 119, Central File, 
1 897-1923, PHS Records. 

17. McClintic to Wyman, 7 July 1911, file 1266, box 119, Central File, 
1 897-1923, PHS Records. 



284 



Notes to Pages 77-81 



18. For biographical information on Cooley see his curriculum vitae, file 
"Zoology and Entomology Bibliography," Archives Department, Renne Li- 
brary, Montana State University, Bozeman; obituary by Glen M. Kohls, 
/. Econ. Entomol. 62. {i^6^):^j2.. For a history of the development of entomol- 
ogy as a graduate program at Massachusetts Agricultural College, see Entomol- 
ogy and Zoology at the Massachusetts Agricultural College (Amherst, Mass.: 
Massachusetts Agricultural College, 191 1) (esp. Warren E. Hinds's article by 
the same title), 15-2.7. This institution later became the University of Mas- 
sachusetts. 

19. Robert A. Cooley, "Notes on Spotted Fever," manuscript, 1953, in RML 
Scrapbook "1942— "; idem, "Preliminary Report on the Wood Tick, Der- 
macentor sp.,'' Montana Agricultural Experiment Station Bulletin no. 75 
(i909):95-i04. Ricketts to Tuttle, 9 November 1908, folder i, "Rocky Moun- 
tain Spotted Fever, 1908-1911," box i, "General Correspondence," MSBH 
Records; Cooley to Tuttle, 16 November 1908, vol. "W. F. Cogswell, A. H. 
McCray, T. D. Tuttle," CC. 

20. The results of the tick survey w^ere published in F. C. Bishopp, "The 
Distribution of the Rocky Mountain Spotted Fever Tick," U.S. Bureau of 
Entomology Circular no. 136 (191 1); W. D. Hunter and F. C. Bishopp, "The 
Rocky Mountain Spotted Fever Tick, with Special Reference to the Problem 
of Its Control in the Bitter Root Valley in Montana," U.S. Bureau of Ento- 
mology Bulletin no. 105 (191 1). On the history of the Bureau of Biological 
Survey, see Jenks Cameron, The Bureau of Biological Survey: Its History, 
Activities, and Organization, Institute for Government Research Service Mon- 
ographs of the United States Government no. 54 (Baltimore: Johns Hopkins 
Press, 1929). 

21. Cooley, "Notes on Spotted Fever," 2—3. Price relates the anecdote in 
more detail in Fighting Spotted Fever (see chap. 3, n. 4), 74-76. Birdseye 
succeeded in publishing as first author of one paper and as junior author of 
another, but King did not. His work, although acknowledged, appeared in 
191 1 under the authorship of Cooley and representatives of the Bureau of 
Entomology. See citations in n. 22, 24, and 27 below. King wrote to Cooley 
about Bishopp's claiming of first-author status in King to Cooley, 23 December 
19 1 2, vol. "W. V. King," CC. 

22. Robert A. Cooley, "Tick Control in Relation to the Rocky Mountain 
Spotted Fever: A Report of Cooperative Investigations Conducted by the 
Bureau of Entomology and the Montana Experiment Station," Montana Ag- 
ricultural College Experiment Station Bulletin no. 85 (1911):! 8-19. 

23. Ibid., 20. Although the men noted that they used a "woolen" cloth, 
flannel was soon adopted to flag ticks because it is much lighter and easier to 
handle. Game Warden J. L. DeHart reminded Cooley in 19 14 about "the 
wanton slaughter of game in 19 10 by Mr. Birdseye's party." See DeHart to 
Cooley, 7 August 19 14, vol. "Montana State Officials," CC. 

24. Cooley, "Tick Control," 20-27; Cooley to W. E. McMurry, 17 January 
191 1, vol. "Montana State Officials," CC; W. H. Henshaw and Clarence 
Birdseye, "The Mammals of the Bitter Root Valley, Montana and Their Re- 
lation to Spotted Fever," U.S. Bureau of Biological Survey Bulletin no. 82 
(1911). 

25. See correspondence regarding this in vol. "W. F. Cogswell, A. H. McCray, 
T. D. Tuttle," CC. 



Notes to Pages 8i-8j 



285 



26. Cooleyto Norris, 13 October 19 10; and Cooley to McMurry, 17 January 
191 1, vol. "Montana State Officials"; Cooley to H. T. Fernald, 4 May 191 1, 
vol. "Professors at Various Universities"; and Cooley to W. D. Hunter, 23 
May 191 1, vol. "W. F. Cogswell, A. H. McCray, T. D. Tuttle," CC (quotation 
from Cooley to McMurry). 

27. Cooley, "Notes on Spotted Fever," 3; Clarence Birdseye, "Some Com- 
mon Mammals of Western Montana in Relation to Agriculture and Spotted 
Fever," U.S. Department of Agriculture Farmer's Bulletin no. 484 (1912). 

28. Cooley, "Notes on Spotted Fever," 4. According to the entomologists' 
version of this larger controversy, Tuttle later made outrageous and false 
charges about the dangerous conditions under which this experiment was 
conducted. See Cooley to King, 13 May 19 12, vol. "W. V. King," CC; King 
to Cooley, 3 May 1912, file 1266, box 119, Central File, 1897— 1923, PHS 
Records. 

29. Cooley, "Tick Control," 27-28; Thomas D. Tuttle, untitled statement 
opposing Cooley's independent work, n.d., folder i, "Rocky Mountain Spotted 
Fever, 1908— 191 1," box i, "General Correspondence," MSBH Records. 

30. MSBH Minutes, 5 June 191 1. 

31. Thomas D. Tuttle, untitled statement opposing Cooley's independent 
work (see n. 29 above); MSBH Minutes, 24 July 191 1. 

32. King to Cooley, 3 May 19 12; and Cooley to King, 13 May 191 2, vol. 
"W. V. King," CC; MSBH Minutes, 6 June 191 1; Montana State Archives. 
Howard to Cooley, 29 May 191 1, vol. "W. F. Cogswell, A. H. McCray, 
T D. Tuttle," CC. 

33. Thomas B. McCHntic, "Investigations of and Tick Eradication in Rocky 
Mountain Spotted Fever: A Report of Work Done on Spotted Fever in Co- 
operation with the State Board of Health of Montana," Pub. Health Rep. 27 
(i9i2):732-6o. 

34. Ibid., 734. 

35. Ibid., 735; H. W. Graybill, "Methods of Exterminating the Texas Fever 
Ticks," U.S. Department of Agriculture Farmer's Bulletin no. 378 (1909). 
After the Florence vat was dynamited in 191 3, it was replaced by a galvanized 
iron vat. 

36. McClintic, "Investigations and Tick Eradication," 735-36. 

37. Ibid., 736-38. 

38. Ibid., 733—34; Harden, Inventing the NIH (see chap. 3, n. 35), 27-39; 
Manfred Waserman, "The Quest for a National Health Department in the 
Progressive Era," Bull. Hist. Med. 49 (i975):353— 80; George Rosen, "The 
Committee of One Hundred on National Health and the Campaign for a 
National Health Department, 1906— 19 12," American Journal of Public Health 
62 (i972):26i-63. 

39. Entry dated 21 November 191 1, Hygienic Laboratory Registers, NLM; 
Harden, Inventing the NIH, 38-39; An Act to Change the Name of the Public 
Health and Marine Hospital Service, to Increase the Pay of Officers of Said 
Service, and for Other Purposes, 14 August 19 12, 37 Stat. L. 309. 

40. Various secondary sources contain conflicting accounts of McClintic's 
marriage and death from spotted fever. My account is based largely on a letter 
seeking a pension for McClintic's widow and initialed by Service administrators 
who knew McClintic personally: Andrew Mellon to Harold Knutson, 5 Feb- 
ruary 1930, McClintic personnel file, NARA, Saint Louis. 



286 



Notes to Pages 86-pi 



41. McClintic, "Investigations and Tick Eradication," 746-47; L. D. Pricks, 
ed., "Rocky Mountain Spotted Fever: Some Investigations Made During 19 12 
by Passed Asst. Surg. T. B. McClintic," Pub. Health Rep. 29 ( 19 14) : 1008- 
20. 

42. Pricks, ed., "Rocky Mountain Spotted Pever: McClintic," 1012, 1019- 
20; McClintic, "Investigations and Tick Eradication," 744-46. Experiments 
with coyotes and domestic cats gave inconclusive results. 

43. McClintic, "Investigations and Tick Eradication," 740-42; Pricks, ed., 
"Rocky Mountain Spotted Pever: McClintic," 1012-19. 

44. Pricks, ed., "Rocky Mountain Spotted Pever: McClintic," 1009-12. 

45. Andrew^ Mellon to Harold Knutson, 5 February 1930, McClintic per- 
sonnel file, NARA, Saint Louis; "Specialist Dies on Day of Arrival at Wash- 
ington," Northwest Tribune, 16 August 19 12; "Dr. McClintic Dies after Long 
Journey," Western News, 16 August 191 2; "Spotted Pever," Western News, 
3 September 19 12. 

46. Por biographical information on Pricks see Williams, United States Public 
Health Service (see chap. 3, n. 39), 195, 296, 302, 545, 559; Pricks's personnel 
file, Record Group 090—78, Accession no. 0001, Agency Box no. OP, Records 
Center Location no. PU#i34867 through PU#i34992, box # 41, NARA, 
Saint Louis; "Takes Up Study of the Deadly Spotted Fever Bearing Tick: Passed 
Assistant Surgeon L. D. Pricks Designated to Resume Work of Dr. McClintic, 
Who Caught Malady While Investigating It, and Died," clipping, n.d., RML 
Scrapbook "1919-1931." 

47. Price, Fighting Spotted Fever, 96— ^y, MSBE, First Biennial Report, 6; 
An Act to Create the State Board of Entomology. To Define its Powers and 
Duties and Appropriate Money Therefor, cited in MSBE, First Biennial Report, 
5. 

48. Tuttle obituary in Montana Record Herald (Helena), 9 July 1942. During 
World War I, Tuttle served as director of medical administration at the can- 
tonments of Fort Lew^is and Bremerton, Washington; later he held a post at 
the U.S. Veterans Hospital at Saint Paul, Minnesota. He died on 24 June 1942 
at age seventy-three from heart disease. 

49. Tuttle to W. C. Rucker, 23 September 1913, file 1266, box 119, Central 
File, 1 897-1923, PHS Records. Por biographical information on Cogsw^ell see 
John S. Anderson, "A Strange Disease in a Beautiful Land," Treasure State 
Health, Pall 1976, 13-16; obituary in JAMA 161 (i956):i494. 

50. MSBH Minutes, 16 December 19 12; Price, Fighting Spotted Fever, 96- 
97- 

51. Price, Fighting Spotted Fever, 98-103; Hunter to Cooley, 31 March 
1913, folder 2, "Rocky Mountain Spotted Pever, 1912— 1919," box i, "General 
Correspondence," MSBH Records. 

52. W. V. King, "Work of Bureau of Entomology against Spotted Fever Tick 
in Co-operation with Board," in MSBE, First Biennial Report, 18; Pricks to 
Montana State Board of Entomology, 14 May 191 5, vol. "Montana State 
Officials," CC; "Start War on Wood Tick," Northwest Tribune, 18 April 
1913. 

53. Robert A. Cooley, "Communication from the State Entomologist to the 
State Board of Entomology," n.d., folder Ei, "Rocky Mountain Spotted Fe- 
ver—Research and Control (R. A. Cooley), 1909-1916," box 10, ZEA. 

54. Pricks to Blue, 15 September 191 3; and Howard to Blue, 20 August 
1913, file 1266, box 119, Central File, 1897-1923, PHS Records. 



Notes to Pages 91-95 



287 



55. Blue to Howard; and memorandum for the Secretary, signed Rupert 
Blue, 29 September 1913, file 1266, box 119, Central File, 1897-1923, PHS 
Records. 

56. Unsigned letter to Fricks, 1 6 September 1 9 1 3 , file 1 266, box 119, Central 
File, 1 897-1923, PHS Records. The writer appears to have been Surgeon 
General Rupert Blue. 

57. L. D. Fricks, "Rocky Mountain Spotted Fever: A Report of Its Inves- 
tigation and of Work in Tick Eradication for Its Control During 19 13," Pub. 
Health Rep. 29 (i9i4):449-6i (strength of dipping solutions is discussed on 
p. 452); Price, Fighting Spotted Fever., 107. 

58. Price, Fighting Spotted Fever, 107-9. the official ban against com- 
pensation from state funds, see Butler to Cooley, 22 July 1915, vol. "Montana 
State Officials"; also letters regarding compensation in vol. "Numerous Per- 
sons in the Bitterroot Valley," CC. 

59. Known as the "Laboratory Dip," the improved formula had been worked 
out by a South African researcher and included arsenite of soda, soft soap, 
kerosene, and water. See King, "Work of Bureau of Entomology," 20. 

60. These incidents are briefly covered in Price, Fighting Spotted Fever., 1 1 1- 
13. They received scant mention in the press and in official archival corre- 
spondence. See, for example, "Dipping Vats Destroyed," Northwest Tribune, 
20 June 19 1 3, which reported that John Dunbar had been charged with 
destroying the vat on the James Dunbar ranch northwest of Hamilton. Pros- 
ecution of Dunbar is mentioned only briefly in D. M. Kelly to Cooley, 12 
September 191 3, vol. "Montana State Officials"; and destruction of the Flor- 
ence vat is mentioned but not described in Cooley to J. D. Taylor, 24 June 
191 3, vol. "Numerous Persons in the Bitterroot Valley," CC. There is no 
discussion of either incident in the files of the National Archives or in any 
official publications. Robert N. Philip, however, in a personal communication 
to the author, 16 February 1988, illuminated the incident of the dynamiting 
of the Florence vat. His information was based on an interview he conducted 
on 20 February 1986, with Carl Wemple, who had survived spotted fever after 
a prolonged illness. The boys' father, Philip stated, denied having had anything 
to do with the dynamiting. 

61. Cooley to King, i August 191 3, vol. "W. V. King"; and C. H. Stevens 
to Cooley, 3 August 19 13, vol. "Montana State Officials," CC; King, "Work 
of Bureau of Entomology," 17-18. 

62. Fricks, "Rocky Mountain Spotted Fever: A Report, 19 13," 455; King, 
"Work of the Bureau of Entomology," 23. 

63. King, "Work of the Bureau of Entomology," 19—23; Fricks, "Rocky 
Mountain Spotted Fever: A Report, 191 3," 451. 

64. L. D. Fricks, "Rocky Mountain Spotted (or Tick) Fever: Sheep Grazing 
as a Possible Means of Controlling the Wood Tick (Dermacentor andersoni) 
in the Bitter Root Valley," Pub. Health Rep. 28 (191 3): 1647-53 (quotation 
from p. 1649); King to Cooley, 6 November 191 5; and Cooley to King, 19 
November 19 15, vol. "W. V. King," CC. 

65. Fricks, "Rocky Mountain Spotted Fever: A Report, 1913," 454. 

66. Idem, "Rocky Mountain Spotted (or Tick) Fever: Sheep Grazing," 1647— 
49, 1653; idem, "Rocky Mountain Spotted Fever: A Report, 1913," 455. 

67. Idem, "Rocky Mountain Spotted Fever: A Report, 1913," 456; idem, 
"Rocky Mountain Spotted (or Tick) Fever: Sheep Grazing," 1653. 



288 



Notes to Pages 9S-98 



68. W. V. King, "Report on the Investigation and Control of the Rocky 
Mountain Spotted Fever Tick in Montana During 191 5-1 9 16," in MSBE, 
Second Biennial Report, 23; King to Cooley, 6 November 191 5, vol. 
"W. V. King," CC. 

69. "Bitter Root Sheep Come to the Rescue," Western News, 14 April 19 14; 
"Sheep Death on Ticks, Experiments Prove," ibid., 8 May 19 14. 

70. Smith and Kilbourne, "Investigations into Texas or Southern Cattle 
Fever" (see chap. 3, n. 21). 

71. Fricks, "Rocky Mountain Spotted Fever: A Report, 19 13," 452-53. 

72. Cooley to R. R. Parker, 24 May 1915, vol. "R. R. Parker, 1913-1917," 
CC. 

73. Tabulation of spotted fever cases in Montana by county, 191 5, n.d., 
vol. "W. R Cogswell, A. H. McCray, T. D. Turtle," CC; Robert A. Cooley, 
"Control of the Rocky Mountain Spotted Fever Tick in Montana," in MSBE, 
Second Biennial Report, 6; "Report 18 Cases of Spotted Fever," Western News, 
18 May 1915. 

74. R. R. Spencer, "The Fleas, the Ticks, Spotted Fever, and Me," Saturday 
Review 46 (2 November i963):48. Spencer's background will be discussed in 
detail in chap. 7. 

75. For biographical information on Parker see Victor H. Haas, "Ralph R. 
Parker: 1888-1949," Science iii (i95o):56-57; American Men of Science, 
5th ed. (see chap. 3, n. 64), 857; Who's Who in America: A Biographical 
Dictionary of Notable Living Men and Women, 1938-39 (Chicago: Marquis- 
Who's Who, 1939), 1935; "Ralph R. Parker," in Jeanette Barry, comp.. No- 
table Contributions to Medical Research by Public Health Service Scientists: 
A Bibliography to 1940 (Washington, D.C.: Government Printing Office, 
i960), 63-65. 

76. Cooley to Fernald, 10 March 19 14; and Fernald to Cooley, 17 March 
19 14, vol. "Professors at Various Universities," CC; MSBE, First Biennial 
Report, 32-34; R. R. Parker and R. W. Wells, "Some Facts of Importance 
Concerning the Rocky Mountain Spotted Fever Tick (Dermacentor venustus 
Banks) in Eastern Montana," in MSBE, Second Biennial Report, 45-56; 
R. R. Parker, "Second Report on Investigations of the Rocky Mountain Spotted 
Fever Tick in Eastern Montana," in MSBE, Third Biennial Report, 41—54. 
During his 19 17 work, Parker was assisted by young Harold C. Urey, who 
in 1934 won a Nobel prize in chemistry. 

77. "Regulations of the Montana State Board of Entomology," in MSBE, 
Second Biennial Report, 1 1 ; Fricks to Montana State Board of Entomology, 
8 November 19 16, vol. "Montana State Officials"; Cooley to King, 16 De- 
cember 1916; and King to Cooley, 26 and 31 December 1916, vol. "W. V. 
King," CC; Fricks to Blue, 4 December 1916, file 1266, box 119, Central File, 
1897-1923, PHS Records. 

78. Fricks to Cooley, i February 1917, folder 2, "Rocky Mountain Spotted 
Fever, 1912— 1919," box i, "General Correspondence," MSBH Records. 

79. Malburn to Stewart, 12 December 19 16; Cogswell to Malburn, 27 
December 1916; and McAdoo to Cogswell, 10 January 1917, folder 2, "Rocky 
Mountain Spotted Fever, 1912-1919," box i, "General Correspondence," 
MSBH Records. 

80. Fricks to Blue, 9 April 19 17; Blue to Fricks, 24 April 19 17; Blue to 
Cogswell, 24 April 1917; and "Tick Quarantine in Valley Lifted by State 



Notes to Pages pp-ioz 



289 



Board," clipping from Daily Missoulian, n.d., file 1266, box 119, Central File, 
1897— 1923, PHS Records; "Tick Quarantine Is Lifted along the West Side," 
Western News, 12 April 19 17. 

81. Cooley to Rankin, 17 July 19 17; and Secretary of Agriculture David F. 
Houston to Rankin, 12 September 19 17, vol. "Montana State Officials," CC. 

82. Cooley to S. Burt Wolbach, z6 February 19 18, vol. "Professors at Various 
Universities," CC. On Parker's work at Harvard and an illness he suffered 
during this period, see his correspondence with Cooley from August through 
November 1917, vol. "R. R. Parker, 1913-1917"; and Parker to Cooley, 12 
and 30 March 1918, vol. "R. R. Parker, 1918-1919," CC. 

83. Parker to Cooley, 25 April 1918, vol. "R. R. Parker, 1918-1919," CC; 
"Controlling the Tick," Western News, 6 March 1919; Robert A. Cooley, 
"Control Methods in Use," in MSBE, Third Biennial Report, 6; R. R. Parker, 
"Report of Tick Control Operations in the Bitter Root Valley during the Season 
of 19 1 8, Facts in Connection Therewith; Recommendations for the Further 
Prosecution of the Work," in MSBE, Third Biennial Report, 25-40; R. R. 
Parker, "Report of Tick Control Operations in the Bitter Root Valley during 
the Seasons of 1919 and 1920," in MSBE, Fourth Biennial Report, 18—44. 

84. Parker to Cooley, 27 January 1919; and correspondence in April 1919 
between Parker and Cooley on stock owners' opposition to grazing restrictions, 
vol. "R. R. Parker, 1918-1919," CC; Robert A. Cooley, "Results," in MSBE, 
Third Biennial Report, lo-ii, 17. 

85. Robert A. Cooley, introductory remarks in MSBE, Fourth Biennial 
Report, 5; idem, in Fifth Biennial Report, 4; Price, Fighting Spotted Fever, 
169. The Montana State Board of Entomology did not publish a report to 
cover the year 1921. 

86. Robert A. Cooley, letter of transmittal, in MSBE, Fourth Biennial Report, 
4. The possible extermination of the mountain goat was first proposed in 
Cooley, "Control Methods," 7. See also idem, "The Goat Question," press 
release, 18 September 1923, folder E4, "Rocky Mountain Spotted Fever and 
General and Miscellaneous Health Services, 1925— 1946," box 10, ZEA; "The 
Mountain Goat or the Taxpayers Goat," Northwest Tribune, 12 October 
1923, clipping in RML Scrapbook "1919— 1931." 

87. Cogswell to Surgeon General Gumming, telegram, 22 June 192 1, cited 
in Price, Fighting Spotted Fever, 169; "Spotted Fever Causes 2 Deaths," West- 
ern News, 9 June 1921; "Tyler Worden of Missoula Dies," Western News, 
16 June 1921. I am grateful to Robert N. Philip for information about the 
epidemiology of the 1921 cases. 

Chapter Six: A Wholly New Type of Microorganism 

1. For a statement of Koch's postulates, see chap. 3, n. 22; see also Victoria 
A. Harden, "Koch's Postulates and the Etiology of Rickettsial Diseases," 
/. Hist. Med. Allied Sci. 42 (198 7): 277-9 5. 

2. E. R. LeCount, "A Contribution to the Pathological Anatomy of Rocky 
Mountain Spotted Fever," /. Inf. Dis. 8 (i9ii):42i— 26 (quotations from pp. 
422, 423, 424). 

3 . On Councilman and Mallory see Esmond R. Long, A History of American 
Pathology (Springfield, 111.: Charles C. Thomas, 1962), 153—55. biograph- 
ical information on Wolbach see Charles A. Janeway, "S. Burt Wolbach, 1880- 



290 



Notes to Pages 103-s 



1954," Trans. Assn. Am. Physicians 67 (i954):30-35; Shields Warren, "Sim- 
eon Burt Wolbach, 3rd July 1880— 19th March 1954," Journal of Pathology 
and Bacteriology 68 {i9$4):6$6-^'j; Sidney Farber and Charlotte L. Maddock, 
"S. Burt Wolbach, M.D., 1 880-1954," A.M. A. Archives of Pathology S9 
(195 5)1624-30; "S. Burt Wolbach," in Esmond R. Long, History of the Amer- 
ican Society for Experimental Pathology (Bethesda, Md.: American Society 
for Experimental Pathology, 1972), 89-90; "Dr. S. B. Wolbach, Pathologist, 
Dies," New York Times, 20 March 1954; Jeffrey D. Hubbard, "S. Burt Wol- 
bach, M.D., 1 880-1954," Pediatric Pathology 7 (1987): 507-14. 1 am grateful 
to Dr. Hubbard for providing me with a preprint of his paper. 

4. Wolbach, "Studies on Rocky Mountain Spotted Fever," 55, as cited in 
chap. 4, n. 7. 

5. For biographical information on Noguchi see Isabel R. Plesset, Noguchi 
and His Patrons (Rutherford, N.J.: Fairleigh Dickinson University Press, 1980); 
Gustav Eckstein, Noguchi (New York: Harper, 193 1); Paul Franklin Clark, 
"Hideyo Noguchi, 1 876-1928," Bull. Hist. Med. 33 (1959): 18-19. My dis- 
cussion of Noguchi's early spotted fever work follows Plesset, Noguchi, 166- 
73- 

6. Hideyo Noguchi, Snake Venoms: An Investigation of Venomous Snakes 
with Special Reference to the Phenomena of Their Venoms (Washington, D.C.: 
Carnegie Institution of Washington, 1909); idem, "A Method for the Pure 
Cultivation of Pathogenic Treponema Pallidum [Spirocheta pallida),'' Journal 
of Experimental Medicine 14 (i9ii):99-io8; Plesset, Noguchi, 166; Noguchi 
to Fricks, 15 February 19 16, file "S. F. History (Correspondence with Noguchi, 
1916)," RML Research Records. Tsutsugamushi is discussed in more detail 
later in this chapter. 

7. L. D. Fricks, "Rocky Mountain Spotted Fever: A Report of Laboratory 
Investigations of the Virus," Pub. Health Rep. 31 (i9i6):5i6— 21, reprinted 
in MSBE, Second Biennial Report, 28-34 (quotations from the latter, p. 33). 

8. Wolbach to Cogswell, 21 February 1916, folder 2, "Rocky Mountain 
Spotted Fever, 19 12-19 19," box i, "General Correspondence," MSBH Re- 
cords; Wolbach to Cooley, 21 February and 21 April 19 16; Cooley to Wolbach, 
telegram, i March, and letter, 8 June 19 16, vol. "Professors at Various Uni- 
versities"; and Cogswell to Wolbach, 29 April 1916, vol. "W. F. Cogswell, 
A. H. McCray, T. D. Turtle," CC. 

9. "I hastened into print," Wolbach confided in a letter to Fricks, "because 
of Noguchi's competition." See Wolbach to Fricks, 21 April 1916, file "S. F. 
History (Correspondence with Wolbach — 1916)," RML Research Records. 

10. Wolbach to Cooley, 14 November 1916, vol. "Professors at Various 
Universities," CC. 

U.S. Burt Wolbach, "The Etiology of Rocky Mountain Spotted Fever (A 
Preliminary Report)," /. Med. Res. 34 (i9i6):i2i-25 (quotations from pp. 
122-23), reprinted in MSBE, Second Biennial Report, 35-44; idem, "The 
Etiology of Rocky Mountain Spotted Fever: Occurrence of the Parasite in the 
Tick (Second Preliminary Report),"/. Med. Res. 35 (i9i6):i47— 50. 

12. Plesset, Noguchi, 170-71; Noguchi to Fricks, 16 October 19 16, file 
"S. F. History (Correspondence with Noguchi — 19 16)," RML Research Re- 
cords. 

13. Wolbach to Cooley, 13 May 1918, vol. "Professors at Various Univer- 
sities," CC. 



Notes to Pages 106—8 



14. McCoy to Fricks, i May and 12 June 19 16, file "S. F. History (Cor- 
respondence, McCoy and Fricks— General — 1916)," RML Research Records. 

15. Wolbach to Cooley, 13 December 19 16, vol. "Professors at Various 
Universities," CC. 

16. S. Burt Wolbach, "The Etiology and Pathology of Rocky Mountain 
Spotted Fever: The Occurrence of the Parasite and the Pathology of the Disease 
in Man; Additional Notes on the Parasite (Third Preliminary Report),"/. Med. 
Res. 37 (i9i8):499-5o8 (quotation from p. 501). 

17. Ibid.; Wolbach to Chairmen of the State Boards of Entomology and 
Health, 18 January 19 18, vol. "Professors at Various Universities," CC (quo- 
tation from the letter). 

18. Wolbach to Cooley, 20 February 191 8, vol. "Professors at Various 
Universities," CC. 

19. Parker to Cooley, 4 June 191 8, vol. "R. R. Parker, 19 18-19 19"; 
Wolbach to Cooley, 2 November 19 18, vol. "Professors at Various Univer- 
sities," CC. 

20. My discussion of Molinscek's illness is based on his hospital report, 
folder "Molinscek," box 20, Record Group no. 210.3, Rockefeller University 
Archives, New York; and on Plesset's discussion of the accident in Noguchi, 
173- 

11. The records on Molinscek's death also provide an interesting view^ of 
legal and societal attitudes toward institutional responsibility for the families 
of people who died from laboratory-acquired infections. Under the New York 
labor laws in force at the time of Molinscek's death, the Rockefeller Institute 
had no legal responsibility to provide financial remuneration to his wife and 
daughter, both named Mary. As the institute's attorney advised its officials, 
however, there was a "moral obligation" to do so, and failure to provide 
something might precipitate "attacks from persons hostile to the Institute." 
Consequently, the board of trustees settled a pension on Molinscek's family 
that was more liberal than prevailing Workmen's Compensation requirements 
for deaths covered by the law. See copies of the final financial arrangement 
approved by members of the Executive Committee of the Board of Scientific 
Directors of the Rockefeller Institute dated 29 June 19 18, folder "MoHnscek," 
box 20, Record Group no. 210.3, Rockefeller University Archives, New York. 

22. Wolbach, "Studies on Rocky Mountain Spotted Fever," 83, 87 (see chap. 
4, n. 7). 

23. Ibid., 84. 

24. E. V. Cowdry, "The Distribution of Rickettsia in the Tissues of Insects 
and Arachnids," /. Exp. Med. 37 (i923):43i-56 (quotation from pp. 431- 
32). The first major work on the laboratory regulation of acidity levels, or 
pH, was William Mansfield Clark, The Determination of Hydrogen Ions: An 
Elementary Treatise on the Hydrogen Electrode, Indicators, and Supplemen- 
tary Methods, with an Indexed Bibliography on Applications (Baltimore: 
Williams & Wilkins Co., 1920). 

25. Fricks consistently denied that the two organisms were the same. When 
the Montana State Board of Entomology published the two reports side by 
side, Fricks complained. "I wish to disclaim any connection with the bacillus 
first reported by Prof. Wolbach, and at the same time remind the Board that 
the small, double granules or protozoan bodies" were "first described by me." 



292 



Notes to Pages lop-iz 



See Fricks to the Montana State Board of Entomology, 29 March 19 17, vol. 
"Montana State Officials," CC. 

26. Harry Plotz, "The Etiology of Typhus Fever (and of Brill's Disease)," 
JAMA 62 (i9i4):i556; Henrique da Rocha Lima, "Beobachtungen bei Fleck- 
typhuslausen," Archiv fur Schiffs- und Tropen-Hygiene 21 (1916): 17—31; 
Henrique da Rocha Lima, "Zur Aetiologie des Fleckfiebers," Berl. klin. 
Wchnschr. 53 (19 16) 15 67-72, Eng. trans, in Nicholas Hahon, ed.. Selected 
Papers on the Pathogenic Rickettsiae (Cambridge, Mass.: Harvard University 
Press, 1968), 74-78 (quotation from pp. 'j6—jy). Da Rocha Lima's articles 
on typhus are also reproduced in Henrique da Rocha Lima, Estudos sobre o 
Tifo Exantemdtico, comp. Edgard de Cerqueira Falcao, with commentary by 
Otto G. Bier (Sao Paulo, Brazil, 1966). 

27. Wolbach, "Studies on Rocky Mountain Spotted Fever," 87-88. 

28. A. Conor and A. Bruch, "Une Fievre eruptive observee en Tunisie," 
Bulletin de la Societe de Pathologie Exotique et de Ses Filiales 3 (19 10) 1492- 
96 (hereafter cited as Bull. Soc. Path. Exotique)., Eng. trans, in Hahon, ed.. 
Selected Papers, 47-52 (quotations from pp. 47-48). 

29. Nathan E. Brill, "A Study of 17 Cases of a Disease Clinically Resembling 
Typhoid Fever, but without the Widal Reaction," New York Medical Journal 
67 (i898):48-54, 77-82; idem, "An Acute Infectious Disease of Unknown 
Origin: A Clinical Study Based on 221 Cases," Am. J. Med. Sci. 139 
(i9io):484-502. 

30. Jose F. Sant'Anna, "On a Disease in Man Following Tick Bites and 
Occurring in Louren^o Marques," Parasitology 4 (i9ii):87— 88. 

31. George H. F. Nuttall, "On Symptoms Following Tick-Bites in Man," 
Parasitology 4 ( 1 9 1 1 ) : 8 9-9 3 . 

32. J. G. McNaught, "Paratyphoid Fevers in South Africa," Journal of the 
Royal Army Medical Corps 16 (i9ii):505-i4. 

33. J. W. D. Megaw, "A Case of Fever Resembling Brill's Disease," Indian 
Medical Gazette 52 (19 17): 15-18 (quotation from p. 18.. 

34. Oliver Smithson, "Mossman Fever," Journal of Tropical Medicine and 
Hygiene 13 (i9io):35i— 52. A review of reports from the Federated Malay 
States is in WiUiam Fletcher, "Typhus-Like Fevers of Unknown Etiology, with 
Special Reference to the Malay States," Proceedings of the Royal Society of 
Medicine 23 (1930): 1021—27 (discussion, pp. 1027—30). 

3 5 . My discussion follows Francis G. Blake, Kenneth F. Maxcy, J. F. Sadusk, 
G. M. Kohls, and E. J. Bell, "Studies on Tsutsugamushi Disease (Scrub Typhus, 
Mite-Borne Typhus) in New Guinea and Adjacent Islands: Epidemiology, 
Clinical Observations, and Etiology in the Dobadura Area," American Journal 
of Hygiene 41 (i945):243-72; J. R. Audy, Red Mites and Typhus (London: 
Athlone Press, 1968); and Rinya Kawamura, "Studies on Tsutsugamushi Dis- 
ease," College of Medicine of the University of Cincinnati Medical Bulletin 4 
(1926), special nos. i, 2. 

36. Percy M. Ashburn and Charles F. Craig, "Comparative Study of Tsut- 
sugamushi Disease and Spotted or Tick Fever of Montana," Boston Medical 
and Surgical Journal 159 (1908) 1749-61. 

37. The three initial papers describing trench fever were H. Topfer, "Zur 
Aetiologie des 'Febris Wolhynica,' ''Berl. klin. Wchnschr. 53 (19 16): 3 23; idem, 
"Der Fleckfiebererreger in der Laus," Deutsche Medizinische Wochenschrift 
42 (19 1 6): 1 25 1— 54 (hereafter cited as Deutsche med. Wchnschr.)-, and idem. 



Notes to Pages iiz-i^ 



293 



"Zur Ursache und Ubertragung des Wolhynischen Fiebers," Muenchener Med- 
izinische Wochenschrift 63 (19 16): 1495-96. For reviews of trench fever re- 
search written shortly after World War I, see David Bruce, "Trench Fever: 
Final Report of the War Office Trench Fever Investigation Committee," /owrw*^/ 
of Hygiene 20 (i 921): 25 8-8 8; American Red Cross Medical Research Com- 
mittee, Trench Fever: Report of Commission, Medical Research Committee, 
American Red Cross, by Richard R Strong (Oxford: Oxford University Press, 
191 8); H. R Swift, "Trench Fever," Archives of Internal Medicine 26 

(1920) :76-98. 

38. "Typhus Fever and Plague in Central Europe," /AMA 99 (i932):i369. 

39. The report of their work is in League of Red Cross Societies, Typhus 
Research Commission to Poland, The Etiology and Pathology of Typhus^ by 
S. Burt Wolbach, John L. Todd, and Francis W Palfrey (Cambridge, Mass.: 
League of Red Cross Societies, Harvard University Press, 1922) (hereafter cited 
as Wolbach, Todd, and Palfrey, Etiology and Pathology of Typhus). 

40. Parker to Cooley, 14 October 1919; and Parker to Wolbach, 2 December 
1919, vol. "R. R. Parker, 1918-1919," CC. Parker's illness is referred to 
variously as influenza and pneumonia; it may well have been a combination. 
See vol. "R. R. Parker, 1920," CC. 

41. Wolbach to Cooley, 26 August 1920, vol. "Professors at Various Uni- 
versities," CC. On Bacot see J. C. G. Ledingham, "In Memoriam: Arthur W 
Bacot, F. E. S.," British Journal of Experimental Pathology 3 (i922):ii7-24. 

42. Wolbach, Todd, and Palfrey, Etiology and Pathology of Typhus., 3. 

43. Wolbach, "Studies on Rocky Mountain Spotted Fever," 183; Wolbach, 
Todd, and Palfrey, Etiology and Pathology of Typhus., 202. 

44. Wolbach, Todd, and Palfrey, Etiology and Pathology of Typhus., 123— 
24. One point of disagreement about the definition of Rickettsia-bodies con- 
cerned human pathogenicity. Wolbach maintained that only pathogenic or- 
ganisms should be classified as Rickettsia-bodies. Edmund V. Cowdry of the 
Rockefeller Institute, in contrast, argued that this was not a necessary criterion. 
For Cowdry's view see E. V. Cowdry, "Rickettsiae and Disease," Archives of 
Pathology and Laboratory Medicine 2 (1926): 59— 90. 

45. Report of Berlin correspondent, /AMA 76 (i92i):i78o; D. Montfallet, 
"A Protozoon in Relation to Typhus," Revista Medica de Chile 48 (i92o):7i8, 
as abstracted in ibid., 900. 

46. This work was mentioned and rebutted in Peter K. Olitsky, "Definition 
of Experimental Typhus in Guinea-Pigs," ibid. 78 (i922):57i-74. 

47. H. M. Woodcock, " 'Rickettsia'-Bodies as a Result of Cell-Digestion or 
Lysis,"/. Royal Army Med. Corps 40 (i923):8i-97, 241—69; idem, "On the 
Modes of Production of 'Rickettsia'-Bodies in the Louse," ibid. 42 (i924):i2i- 
31, 175—86 (quotation from p. 186); Leo Loewe, Saul Ritter, and George 
Baehr, "Cultivation of Rickettsia-Like Bodies in Typhus Fever," JAMA 77 

(1921) :i967-69. 

48. Edmund Weil and Arthur Felix, "Zur serologischen Diagnose des Fleck- 
fiebers," Wiener klinische Wochenschrift 29 (19 16): 3 3-3 5, Eng. trans, in Ha- 
hon, ed.. Selected Papers., 79-86. 

49. My description follows Hahon's comments in preface to Weil and Felix's 
article, in Hahon, ed.. Selected Papers, 79. 

50. W.J. Wilson, "Serologic Test in Typhus," Lancet i (i922):222; Fletcher, 
"Typhus-Like Fevers," 1024. 



294 



Notes to Pages iij-iy 



51. Report of Berlin correspondent, /AMA 76 (i92i):i78o; B. Fejgin, "Au 
sujet du serum de Kuczynski et d'une variation du Proteus X19 obtenue a 
partir de Rikettsia provazeki," Comptes Rendus des Seances de la Societe de 
Biologie et de Ses Filiales 95 (i926):i2o8-io (hereafter cited as Compt. rend. 
Soc. de bioL); L. Anigstein and R. Amzel, "Recherches sur I'etiologie du typhus 
exanthematique. Le typhus exanthematique chez les cobazes infectes par les 
cuhures du germe," Comt. rend. Soc. de biol. 96 (1927): 1502; M. H. Kuczynski 
and Ehsabeth Brandt, "Neue atiologische und pathogenetische Untersuchun- 
gen in der 'Rickettsiengruppe,' " Krankheitsforschung 3 (19 26) 126-74; Kuc- 
zynski and Brandt, Die Erreger des Fleck- und Felsenfiebers, Biologische und 
Pathogenetische Studien (BerHn: Juhus Springer, 1927); abstract of M. Ruiz 
Castaneda and S. Zia, "Antigenic Relationship of Proteus X19 to Typhus 
Rickettsiae," in Arch. Pathol. 16 (i933):4i9. Elisabeth Brandt's death was 
noted in Richard Otto, "Fleckfieber und Amerikanisches Felsengebirgsfieber," 
Centralblatt fiir Bakteriologie, Parasitenkunde, und Infektionskrankheiten 
106 (i928):279— 91. Theodore E. Woodward, who knew Felix, communicated 
to me that Felix never gave up his conviction that the etiological agent of 
typhus was a variant of B. proteus. 

52. Frederick Breinl, "Betrachtungen, iiber die Immunitat bei einigen Er- 
krankungen mit ultravisiblem Erreger," Deutsche med. Wchnschr. 51 
(i925):264; Rudolf Weigl, "Der Gegenwartige Stand der Rickettsiafor- 
schung," Klinische Wochenschrift 3 (i924):i59o— 94, 1636-41; abstract of 
I. W. Hach, "Experimental Typhus. IV. Filterability of Virus of Typhus," in 
Arch. Pathol. Lab. Med. 3 (i927):3i8; abstract of P. Fiauduroy, "Etiology 
of Typhus," in "Recent Research on Typhus," JAMA 85 (i925):i844; E. V. 
Cowdry, "Rickettsiae and Disease," Arch. Pathol. Lab. Med. 2 (1926): 59- 
90 (reference to Trench Fever Commission on p. 63). 

53. S. B. Wolbach and M. J. Schlesinger, "The Cultivation of the Microor- 
ganisms of Rocky Mountain Spotted Fever {Dermacentroxenus rickettsi) and 
of Typhus {Rickettsia prowazeki) in Tissue Plasma Cultures," /. Med. Res. 
44 (i923):23i-56; P. K. Olitsky and J. E. McCartney, "Experimental Studies 
on the Etiology of Typhus Fever. V. Survival of the Virus in Collodion Sacs 
Implanted Intra-Abdominally in Guinea Pigs,"/. Exp. Med. 38 (i928):69i; 
Clara Nigg and Karl Landsteiner, "Studies on Cultivation of Typhus Fever 
Rickettsia in Presence of Live Tissue," /. Exp. Med. 55 (i932):563-76. 

54. S. Burt Wolbach, "The Rickettsiae and Their Relationship to Disease," 
JAMA 84 (i925):723— 28 (quotations from pp. 723, 728). 

55. Quoted in Hughes, The Virus (see chap. 3, n. 23), 86. 

56. W. G. MacCullum, "A Survey of Our Present Knowledge of Filterable 
Viruses," Arch. Pathol. Lab. Med. i (1926)1487-88 (quotations from p. 488). 
An excellent view of the development of virology is offered in Saul Benison, 
Tom Rivers: Reflections on a Life in Medicine and Science (Cambridge: MIT 
Press, 1967); on this early period see esp. chaps. 3-6. Rivers's views on the 
state of knowledge regarding virus diseases were similar to those of Mac- 
Cullum; see excerpts from a paper on the subject given by Rivers at a sym- 
posium sponsored by the Society of American Bacteriologists in Benison, Tom 
Rivers., 1 10— 1 1 ; the entire text is in T. M. Rivers, "Filterable Viruses: A Critical 
Review," Arch. Pathol. Lab. Med. 3 (i927):525-28. 

57. "Dwarf Bacteria and Pigmy Protozoa," JAMA 94 (i93o):795-96. 

58. Wendell M. Stanley, "Isolation of a Crystalline Protein Possessing the 
Properties of Tobacco-Mosaic Virus," Science 81 (193 5): 644-45; Lily E. Kay, 



Notes to Pages iiy-io 



295 



"W. M. Stanley's Crystallization of the Tobacco Mosaic Virus, 1930-1940," 
his 77 (i986):450-72. 

59. Earlier definitions of "life" turned on the ability of organisms to me- 
tabolize and to reproduce themselves independently. Viruses cannot perform 
these functions alone but must take over the genetic machinery of a functioning 
cell. Sally Smith Hughes observed, "With regard to the nature of viruses, 
biochemical findings appeared to support the idea that viruses are very large 
molecules, a refinement of the nonmicrobial concept of the virus. Yet it was 
also true that the ability of viruses to multiply and to infect were properties 
traditionally associated with the living state. Hence they possessed both an- 
imate and inanimate characteristics." See Hughes, The Virus, 89-92. 

60. Virus and Rickettsial Diseases, with Especial Consideration of Their 
Public Health Significance, Proceedings of a symposium. Harvard School of 
Public Health, 12-17 June ^939 (Cambridge, Mass.: Harvard University Press, 
1940). 

61. S. Burt Wolbach, "The Rickettsial Diseases: A General Survey," ibid., 
797-801. Wolbach also noted that heartwater disease of sheep, goats, and 
cattle was the single rickettsial infection known to infect animals. Its etiological 
agent was known as R. ruminantium, and its vector was the tick Amblyomma 
hebraeum. 

6z. Emile Brumpt, Precis de Parasitologie (Paris: Masson et Cie., 1927), 
883; Henry Pinkerton, "Criteria for the Accurate Classification of the Rick- 
ettsial Diseases (Rickettsioses) and of Their Etiological Agents," Parasitology 
28 (i936):i72-89 (quotation from pp. 185-86); C. B. Philip, "Nomenclature 
of the Pathogenic Rickettsiae," Am. J. Hyg. 37 (i943):3oi-9; Philip, "Family 
Rickettsiaceae Pinkerton," in Bergey's Manual of Determinative Bacteriology, 
7th ed. (Baltimore: Williams & Wilkins, 1957), 934-57. On the evolution of 
rickettsial nomenclature, see also Ida A. Bengtson, "Family Rickettsiaceae 
Pinkerton," in Bergey's Manual of Determinative Bacteriology, 6th ed. (Bal- 
timore: Williams & Wilkins, 1948), 1083-99; Philip, "Nomenclature of the 
Rickettsiaceae Pathogenic to Vertebrates," Ann. New York Acad. Sci. 56 
(i953):484-94. 

Chapter Seven: The Spencer-Parker Vaccine 

1. On land prices see F. J. Clifford to Surgeon General, 26 November 1920; 
and Surgeon General to Clifford, 7 December 1920, folder 3, "Rocky Moun- 
tain Spotted Fever, 1920-1926," box i, "General Correspondence," MSBH 
Records. On tourism, see Cooley to James C. Evenden, 3 May 1922, folder 
E2, "Tick Control— General Correspondence, 1918-1928," box 10, ZEA; 
Cogswell to Fricks, 27 March 1922, file "S. F. History (Correspondence, 
Spencer and Fricks with Others— 19 16-192 5)," RML Research Records. 

2. Charles H. Roberts to Cogswell, 20 July 1921, folder 3, "Rocky Mountain 
Spotted Fever, 1920-1926," box i, "General Correspondence," MSBH Re- 
cords. 

3. Report of Hygienic Laboratory, in MSBH, Tenth Biennial Report, 5; 
Price, Fighting Spotted Fever (see chap. 3, n. 4), 162. 

4. Cogswell to Surgeon General Gumming, and Cogswell to Henry L. Mey- 
ers, telegrams, 22 June 1921, vol. "W. F. Cogswell, A. H. McCray, T. D. 
Tuttle," CC; "U.S. Launches New Fight on Spotted Fever," Montana Record- 
Herald (Helena), 18 July 1921, and "Spotted Fever Aid Is Urged," Montana 



Notes to Pages izo-zj 



Record-Herald, 21 July 192 1; "Would Ask U.S. to Help Fever Fight," Inde- 
pendent (Helena), 22 July 1921, clippings in file 1266, box 120, Central File, 
1897— 1923, PHS Records. 

5. Parran to Cumming, 25 July 1921, folder 3, "Rocky Mountain Spotted 
Fever, 1920-1926," box i, "General Correspondence," MSBH Records. 

6. Cogswell to Parran, 26 August 192 1; and Eliot Wadsworth to Cogswell, 
telegram, 31 August 1921, folder 3, "Rocky Mountain Spotted Fever, 1920- 

1926, " box I, "General Correspondence," MSBH Records. 

7. Fricks to Surgeon General, 24 February 1922, vol. "Montana State Of- 
ficials," CC. 

8. J. W. Kerr to R. R. Spencer, 4 March 1922, folder E9, "Bitter Root Field 
Station, Correspondence, 1922— 1927," box 10, ZEA. For biographical in- 
formation on Spencer see Spencer, "The Fleas, the Ticks, Spotted Fever, and 
Me" cited in chap. 5, n. 74 (quotation from p. 47); R. R. Spencer oral history 
interview by Harlan Phillips, in George Rosen, "Transcripts of Oral History 
Project, 1962— 1964," NLM (hereafter cited as Spencer oral history); Michael 
B. Shimkin, "Historical Note: Roscoe Roy Spencer (i 888-1982)," /owrw^z/ of 
the National Cancer Institute 72 (i984):969-7i; "Roscoe R. Spencer," in 
Barry, Notable Contributions (see chap. 5, n. 75), 79-81; "Roscoe R. Spencer," 
Pittsburgh Medical Bulletin 39 (194 8)1397; Williams, United States Public 
Health Service (see chap. 3, n. 39), 195—99. 

9. Fricks to Cogswell, 22 March 1922; and Cogswell to Fricks, 27 March 
1922, file "S. F. History (Correspondence, Spencer and Fricks with Others — 
1916— 1925)," RML Research Records. 

10. Spencer to J. W. Schereschewsky, 16 March 1922; and Parker to Cooley, 
23 May 1923, folder E9, "Bitter Root Field Station, Correspondence, 1922- 

1927, " box 10, ZEA. 

11. Fricks to J. W. Schereschewsky, 23 November 1923, file "S. F. History 
(Correspondence, Spencer and Fricks with Others— 1916-1925)," RML Re- 
search Records. There was much correspondence about this issue during 1923 
between Parker and Cooley. See folder E9, "Bitter Root Field Station, Cor- 
respondence, 1922-1927," box 10, ZEA. 

12. Spencer to Surgeon General, 10 April and 5 June 1922, file 1266, box 
119, Central File, 1897— 1923, PHS Records. 

13. Spencer to Surgeon General, 5 June 1922, file 1266, box 119, Central 
File, 1 897-1923, PHS Records. This work was published as R. R. Spencer 
and R. R. Parker, "Rocky Mountain Spotted Fever: Infectivity of Fasting and 
Recently Fed Ticks," Pub. Health Rep. 38 (1923): 3 3 3-39. It was reprinted 
as a part of a collection of Spencer and Parker's spotted fever papers in "Studies 
on Rocky Mountain Spotted Fever," U.S. Hygienic Laboratory Bulletin no. 
154 (1930), 1-7. 

14. Spencer to Surgeon General, 5 June 1922; and 10 April 1922, file 1266, 
box 119, Central File, 1 897-1923, PHS Records. 

15. Spencer to Fricks, 15 June 1922, file "S. F. History (Correspondence, 
Spencer and Fricks with Others — 19 16-192 5)," RML Research Records. 

16. "A Hero of the Bitter Root Valley"; and "Research Worker Dies of 
Virulence He Is Combatting," Daily Missoulian, i July 1922, clippings in 
folder E3, "Rocky Mountain Spotted Fever Fatalities, 1922-1928," box 10, 
ZEA; Price, Fighting Spotted Fever (see chap. 3, n. 4), 179-81. 



Notes to Pages 12^-28 



297 



17. Spencer to Surgeon General, 13 April 1923; and Spencer to A. M. 
Stimson, 14 May 1923, file 1266, box 119, Central File, 1 897-1923, PHS 
Records; R. R. Spencer, "Experimental Studies on the Virus of Rocky Moun- 
tain Spotted Fever," in "Rocky Mountain Spotted Fever," Montana State Board 
of Health Special Bulletin no. 26 (i923):40-44; R. R. Spencer and R. R. 
Parker, "Rocky Mountain Spotted Fever: Viability of the Virus in Animal 
Tissues," Pub. Health Rep. 39 (i924):55-57. 

18. Spencer to Surgeon General, 13 April 1923; untitled memo, apparently 
to the surgeon general from G. W. McCoy, 7 May 1923; and Gumming to 
Spencer, 10 May 1923, file 1266, box 119, Central File, 1897— 1923, PHS 
Records. 

19. Hideyo Noguchi, "Immunity Studies of Rocky Mountain Spotted Fever. 

I. Usefulness of Immune Serum in Suppressing an Impending Infection," 
/. Exp. Med. 37 (19 23):3 83-94 (quotations from pp. 383, 394). 

20. Parker to Cooley, 18 November 1922, vol. "R. R. Parker, 1921-1925," 
CC; Noguchi to Cogswell, 30 December 1922, folder 3, "Rocky Mountain 
Spotted Fever, 19 20-1 9 26," box i, "General Correspondence," MSBH 
Records. 

21. Hideyo Noguchi, "Immunity Studies of Rocky Mountain Spotted Fever. 

II. Prophylactic Inoculation in Animals," /. Exp. Med. 38 (1923) 1605-26 
(quotation from p. 625); idem, "Prophylactic Inoculation against Rocky 
Mountain Spotted Fever," in "Rocky Mountain Spotted Fever," Montana State 
Board of Health Special Bulletin no. 26 (i923):44— 47. 

22. Forew^ord, in "Rocky Mountain Spotted Fever," Montana State Board 
of Health Special Bulletin no. 26 (i923):3. 

23. "Dr. H. Noguchi Is Enthusiastic Man," 6 April 1923, clipping marked 
"either Daily Missoulian or Missoula Sentinel''-, and "Spotted Fever Heroes: 
Noguchi's Countrymen Submit to His Serum," Missoula Sentinel, 12 April 
1923, clippings in RML Scrapbook "1919— 1931"; "A Death Gamble: Martyrs 
to Risk Lives to Aid Science," press release in folder 3, "Rocky Mountain 
Spotted Fever, 1920— 1926," box i, "General Correspondence," MSBH Re- 
cords. 

24. Spencer oral history, 59—62; "Annual Report on Rocky Mountain Spot- 
ted Fever Investigations," [1923], file 1266, box 119, Central File, 1897-1923, 
PHS Records. 

25. Parker to Cooley, 12 July 1923, vol. "R. R. Parker, 1921-1925," CC. 

26. Michky lived in the schoolhouse laboratory in order to be available 
twenty-four hours a day. See job description on untitled personnel list, 192 1, 
file 1266, box 119, Central File, 1897-1923, PHS Records. 

27. Cogswell to Noguchi, 7 September 1923; Spencer to Noguchi, 20 Sep- 
tember 1923; and Noguchi to Spencer, 27 September 1923, folder 3, "Rocky 
Mountain Spotted Fever, 1920-1926," box i, "General Correspondence," 
MSBH Records; Spencer to Surgeon General, 15 August 1923; and "Spotted 
Fever Vaccine Fails to Protect Boy," Anaconda Standard, 13 August 1923, 
clipping in file 1266, box 119, Central File, 1897-1923, PHS Records. 

28. Parker to Cooley, 28 February 1925, vol. "R. R. Parker, 1921-1925," 
CC. For Noguchi's later work on spotted fever, see Hideyo Noguchi, "Cul- 
tivation of Rickettsia-Like Microorganisms from the Rocky Mountain Spotted 
FeverTick, Dermacentor andersoni,"" J. Exp. Med. 43 (i926):5i5-32; Hideyo 



298 



Notes to Pages 128-^0 



Noguchi, "A Filter-Passing Virus Obtained from Dermacentor andersoni^'" ]. 
Exp. Med. 44 (1926): i-io. On the yellow fever research that led to Noguchi's 
death, see Plesset, Noguchi (see chap. 6, n. 5), chaps. 21-22; and Claude E. 
Dolman, "Hideyo Noguchi (1876-1928): His Final Effort," Clio Medica 12 
(i977):i3i-45. 

29. R. R. Spencer and R. R. Parker, "Rocky Mountain Spotted Fever: 
Experimental Studies on Tick Virus," Pub. Health Rep. 39 (i924):3027-4o; 
idem, "Rocky Mountain Spotted Fever: Nonfiltrability of Tick and Blood 
Virus," ibid., 3251-55; R. R. Parker and R. R. Spencer, "A Study of the 
Relationship between the Presence of Rickettsialike Organisms in Tick Smears 
and the Infectiveness of the Same Ticks," ibid., 41 (i926):46i-69; idem, 
"Certain Characteristics of Blood Virus," ibid., 1817-22. 

30. Frederick Breinl, "Studies on Typhus Virus in the Louse," /. Inf. Dis. 
34 (1924): 1-12, abstracted in JAMA 82 {19 14): 49^—98. Spencer's accounts 
of his work in developing the vaccine are in Spencer to Esther Gaskins Price 
Ingraham, 10 October 1945, folder E5, "Rocky Mountain Spotted Fever 
History— Correspondence, 1942-1947," box 10, ZEA; Spencer oral history, 
85—87; Spencer, "The Fleas, the Ticks, Spotted Fever, and Me." 

31. Spencer and Parker, "Rocky Mountain Spotted Fever: Experimental 
Studies on Tick Virus," 21—22. There was some debate at first about whether 
the phenol killed or attenuated the organisms, for prevailing opinion argued 
that only attenuated organisms conferred immunity. Guinea pig studies con- 
vinced Spencer that the organism was indeed killed, and he observed, "We 
are inclined to believe that the killed as well as the live virus of Rocky Mountain 
spotted fever can immunize." See R. R. Spencer and R. R. Parker, "Improved 
Method of Manufacture of the Vaccine and a Study of Its Properties," in idem, 
"Studies on Rocky Mountain Spotted Fever," 68-69. 

32. Price, Fighting Spotted Fever., 195—96. Earl W. Malone, who became 
chief vaccine maker, also wanted to take the experimental vaccine, but Spencer 
cautioned him to wait until it was clear how the vaccine affected one person. 
See Spencer to W. L. Jellison, 9 May 1966, NIAID files, NIH Historical Office. 

33. G. W. McCoy, "A Plague-Like Disease in Rodents," Public Health 
Bulletin no. 43 (19 11): 5 3-71; G. W. McCoy and C. W. Chapin,"Further 
Observations on a Plague-Like Disease of Rodents with a Preliminary Note 
on the Causative Agent, Bacterium tularense,'' J. Inf. Dis. 10 (19 12): 6 1-72; 
G. W. McCoy and C. W. Chapin, ''Bacterium tularense, the Cause of a Plague- 
Like Disease of Rodents," Public Health Bulletin no. 5 3 ( 1 9 1 2) : 1 7-23 ; Edward 
Francis, "Deer-Fly Fever, or Pahvant Valley Plague: A Disease of Man of 
Hitherto Unknown Etiology," Pub. Health Rep. 34 (i9i9):2o6i-62; "Tu- 
laremia Francis 1921: A New Disease of Man," U.S. Hygienic Laboratory 
Bulletin no. 130 (1922), 87 pp.; Edward Francis, "Tularemia," JAMA 84 
(i925):i243-5o; Parker to Cooley, 24 August 1924, vol. "R. R. Parker, 1921- 
1925," CC; Price, Fighting Spotted Fever, 194-97. 

34. Untitled personnel list, 1921, file 1266, box 119. Central File, 1897- 
1923, PHS Records; "Tick Worker Succumbs; Spotted Fever Is Fatal," Daily 
Missoulian, 30 October 1924, clipping in notebook "RMSF Laboratory In- 
fections—Book I," R. R. Parker Notebooks, RML Research Records. 

35. "Tick Worker Succumbs," Daily Missoulian, 30 October 1924; Spencer, 
"The Fleas, the Ticks, Spotted Fever, and Me," 49. 



Notes to Pages 130-^6 



299 



36. Noguchi, cited in Spencer to Surgeon General, 28 March 192.5, file 
0425-32, "Spotted Fever— Hamilton, Montana," box 158, "Domestic Sta- 
tions, Hamilton, Montana," PHS Records; R. R. Spencer and R. R. Parker, 
"Rocky Mountain Spotted Fever: Vaccination of Monkeys and Man," Pub. 
Health Rep. 40 (i925):2i59-67; reprinted in idem, "Studies on Rocky Moun- 
tain Spotted Fever," 28-36. 

37. Cooley to Parker, 24 May 1926, vol. "R. R. Parker, 1926-193 1," CC; 
R. R. Spencer and R. R. Parker, "Rocky Mountain Spotted Fever: Vaccination 
of Monkeys and Man," in idem, "Studies on Rocky Mountain Spotted Fever," 
31-32. 

38. Spencer and Parker, "Rocky Mountain Spotted Fever: Vaccination of 
Monkeys and Man," 34-35. 

39. Spencer to Surgeon General, 28 March 1925, file 0425-32, "Spotted 
Fever — Hamilton, Montana," box 158, "Domestic Stations, Hamilton, Mon- 
tana," PHS Records; Parker's cover letter to Surgeon General, 9 April 1926 
in RML, Monthly Report, March 1926. On Spencer's illness see Parker to 
Cooley, 16 March 1926, vol. "R. R. Parker, 1926-193 1," CC. 

40. R. R. Spencer and R. R. Parker, "Results of Four Years' Human Vac- 
cination," in idem, "Studies on Rocky Mountain Spotted Fever," 72-103, esp. 
89—95; [Parker] to Cooley, 7 July 1926, folder 3, "Rocky Mountain Spotted 
Fever, 1920-1926," box i, "General Correspondence," MSBH Records. 

41. Spencer and Parker, "Results of Four Years' Human Vaccination," 75— 
78; Parker to Surgeon General, telegram, 18 August 1926, file 0425-183, 
"Spotted Fever, Hamilton, Montana," box 158, "Domestic Stations — Ham- 
ilton, Montana," PHS Records; Parker to Surgeon General, 31 August 1926, 
folder 3, "Rocky Mountain Spotted Fever, 1920— 1926," box i, "General Cor- 
respondence," MSBH Records; Parker to Surgeon General, 30 September 
1926, RML Monthly Report, August and September 1926 (quotations from 
this report). 

42. Spencer and Parker, "Results of Four Years' Human Vaccination," 81- 
89. 

43. R. R. Parker, "Rocky Mountain Spotted Fever: Results of Ten Years' 
Prophylactic Vaccination," /. Inf. Dis. 57 (i935):78— 93; idem, "Rocky Moun- 
tain Spotted Fever: Results of Fifteen Years' Prophylactic Vaccination," Amer- 
ican Journal of Tropical Medicine 21 (i94i):369-83. 

44. The various methods tried are documented in RML, Monthly Reports; 
RML, Annual Reports; Earl W. Malone, "Methods of Rearing Dermacentor 
andersoni for the Manufacture of Rocky Mountain Spotted Fever Vaccine"; 
Earl W. Malone, "Preparation of Rocky Mountain Spotted Fever Tick-Tissue 
Vaccine," unpublished technical reports, RML; R. R. Spencer and R. R. Parker, 
"Improved Method of Manufacture of the Vaccine and a Study of Its Prop- 
erties," m idem, "Studies on Rocky Mountain Spotted Fever," 63-72. My 
description of the vaccine-making process is based on these documents and 
on Price, Fighting Spotted Fever, 213-21. 

45. As the quantity of vaccine increased over the years, it became necessary 
to arrange for on-site sterility testing. In 1934 technician Max T. McKee 
w^as sent to Bethesda to learn the techniques, and funds w^ere allocated for a 
special room with incubators necessary for the process at the Spotted Fever 
Laboratory in Montana. See RML, Monthly Report, November 1934, 3; RML, 
Annual Report., ^93 5? 3-4- 



300 



Notes to Pages 1^6-40 



46. This article was reprinted as one chapter in Paul de Kruif, Men against 
Death (New York: Harcourt, Brace & Co., 1932), 119-45. 

47. The quotations were noted as objectionable passages in "An Outside 
View of Bitter Root Valley," Ravalli Republican, 31 March 1927, clipping in 
RML Scrapbook "1919-1931." 

48. Ibid.; "Bitter Root Valley Is Up in Arms," Northwest Tribune, 3 March 
1927, clipping in RML Scrapbook "1919-1931"; Knight to Leavitt, 28 Feb- 
ruary 1929, file 0243-183, "Hamilton, Montana, Chamber of Commerce," 
box 44, "Montana Cities and Counties," State Boards of Health, 1924-193 5; 
and Cumming to Parker, 9 March 1929, file 0425-183, "Hamilton, Montana," 
box 158. "Domestic Stations, Hamilton, Montana," PHS Records. 

49. Cogswell to Pearl I. Smith, n.d.; and F. J. O'Donnell to Cogswell, 15 
and 16 April (two letters), 1926, folder 3, "Rocky Mountain Spotted Fever, 
1920— 1926," box I, "General Correspondence," MSBH Records. 

50. Parker to Cooley, 9 August 1926, vol. "R. R. Parker, 1926-193 1," CC. 

51. Parker to Cooley, 18 May 1925; and Parker to Cooley, 29 January 
1926, vol. "R. R. Parker, 1926— 193 1," CC; Cooley to Cogswell, 14 July 1927, 
folder 4, "Rocky Mountain Spotted Fever, 1927-1929," box i, "General 
Correspondence," MSBH Records. 

52. Cooley to Kenneth Ross, 24 April 1925; and Parker to Cooley, 14 May 
1926, folder 3, "Rocky Mountain Spotted Fever, 1920— 1926," box i, "General 
Correspondence," MSBH Records; Cooley's correspondence with Albert B. 
Tonkin, former Wyoming state health officer, vol. "R. R. Parker, 1926-193 1," 
CC. 

53. Cooley to W. J. Butler and Cogswell, 12 February 1926, vol. "W. F. 
Cogswell, A. H. McCray, T. D. Tuttle," CC. 

54. Wolbach to McCoy, 19 October 1926, vol. "R. R. Parker, 1926— 193 1," 
CC; Cogswell to Spencer, 5 November 1926; and Cumming to Cogswell, 16 
November 1926, file 0425-32, "Montana— Spotted Fever— Hamilton," box 
158, "Domestic Stations— Hamilton, Montana," PHS Records. 

55. Cooley to Wolbach, 24 January 1927, vol. "Professors at Various Uni- 
versities," CC; Spencer to Cooley, 16 March 1927; and Cooley to Spencer, 5 
April 1927, folder E7, "U.S. Public Health Service, Correspondence 1927," 
box 10, ZEA; George L. Knight to Scott Leavitt, 28 February 1929, file 0243- 
183, "Hamilton, Montana, Chamber of Commerce," box 44, "Montana Cities 
and Counties," State Boards of Health, 1924-193 5, PHS Records. 

56. Louis Nelson, Harry G. Bullock, Ralph B. Robinson, William S. Schraedl, 
and James A. Shields to Cogswell, 7 April 1927, folder 12, "1912, 1927-29, 
Rocky Mountain Laboratory," box i, "General Correspondence and Subject 
Files, 1908-1949," MSBH Records. 

57. The other plaintiffs were identified as G. A. Gordon, a physician; F. M. 
Hagens, an engineer for the Bitter Root Irrigation District; Ben Ogg, a phar- 
macist; Bert C. Lee, a dentist; and Judge J. M. Self— all residents of Pine Grove. 
See F. J. O'Donnell to Cogswell, 4 April 1927, folder 4, "Rocky Mountain 
Spotted Fever, 1927-1929," box i, "General Correspondence," MSBH Re- 
cords. 

58. Cooley to Cogswell, 2 April 1927; and H. C. Groff to Cogswell, 14 
April 1927, folder 12, "19 12, 1927-29, Rocky Mountain Laboratory," box 
I, "General Correspondence and Subject Files, 1908-1949," MSBH Records. 



Notes to Pages 141—44 



301 



59. "Work on Laboratory Began Here Yesterday," Western News, i6 June 
1927; "Tick Laboratory Hearing July 27," ibid., 14 July 1927; "Pine Grove 
Folk Go to Court in Effort to Rid Lab from Midst," ibid., 30 June 1927; 
"Laboratory Will Be Build [sic] in Pine Grove as Result of Judge's Decision," 
ibid., II August 1927. Quotations from plaintiffs' testimony w^ere taken from 
the transcript of a portion of the proceedings in RML Research Records. 
Cogswell's testimony w^as cited in the JAMA coverage of the case, "Citizens 
Fear Experimental Spotted Fever Ticks," JAMA 89 (1927): 5 30. On final ne- 
gotiations with the Waddells, see Parker to Cooley, 17 June 1927, folder E7, 
"U.S. Public Health Service, Correspondence 1927," box 10, ZEA. 

60. Description in attachment to request for bids to construct laboratory, 
Standard Form no. 33, "Standard Government Short Form Contract," 5 De- 
cember 1927, vol. "W. E Cogswell, A. H. McCray, T. D. Tuttle," CC. 

61. Cooley to Cogswell and Butler, 19 April 1930, vol. "W. F. Cogswell, 
A. H. McCray, T. D. Tutde," CC. 

62. Ibid. 

63. There are numerous accounts of Kerlee's illness and death. Mine is 
drawn primarily from F. J. O'Donnell to Cogswell, 23 February 1928, folder 
4, "Rocky Mountain Spotted Fever, 1927-1929," box i, "General Corre- 
spondence," MSBH Records; Spencer to Surgeon General, 14 February 1928, 
RML, Monthly Report, February 1928; Montana State Board of Health Special 
Spotted [Tick] Fever Report on LeRoy Kerlee, notebook "R.M.S.F. — Labo- 
ratory Infections— Book I," R. R. Parker Notebooks, RML Research Records; 
"Health Secretary Explains Conditions Accounting for Death from Spotted 
Fever," 21 February 1928, clipping in RML Scrapbook "1919-1931." Brian 
Thrailkill, a student associate of Kerlee's in the schoolhouse laboratory, stated 
in an interview with Robert N. Philip, 3 August 1983, that Kerlee probably 
acquired his illness from washing contaminated glassware. Kerlee's family 
were longtime residents of the Bitterroot Valley. His aunt, Bessie K. Monroe, 
wrote a column for the Ravalli Republic until her death in 1987. See B. K. 
Monroe, "The Kerlees of Darby," in Bitter Root Historical Society, ed., Bit- 
terroot Trails (see chap. 2, n. i), 2:290—99. 

64. Montana State Board of Health Special Spotted [Tick] Fever Report on 
LeRoy Kerlee, notebook "R.M.S.F.— Laboratory Infections— Book I," R. R. 
Parker Notebooks, RML Research Records. 

65. "Health Secretary Explains" (see n. 63 above); Spencer to Surgeon 
General, 14 February 1928, RML, Monthly Report, February 1928. 

66. Parker to Cooley, 26 February 1928, vol. "R. R. Parker, 1926-193 1," 
CC; Spencer oral history, 98. 

67. In the published account of this speech, however, Spencer was mentioned 
several times as being a colleague in the work. See R. R. Parker, "Rocky 
Mountain Spotted Fever," in MSBE, Seventh Biennial Report, 39-62. 

68. Spencer oral history, 97-98. 

69. Spencer's popular articles include "The Fleas, the Ticks, Spotted Fever, 
and Me," and "Rocky Mountain Spotted Fever: A Remarkable American 
Malady and Its Insect Vector," Hygeia 4 (i926):46i-63. 

70. Fricks to Surgeon General, 13 August 1929; Gumming to Fricks, 24 
September 1929; and A. M. Stimson to "Dr. Pierce," memorandum, 20 Sep- 
tember 1929, file 1850-95, "Rocky Mountain Spotted Fever Laboratory," 



302 



Notes to Pages 144— 4 p 



box 158, "Domestic Stations, Hamilton, Montana," PHS Records. Parker's 
industrious habits eventually received favorable comment from Fricks himself. 
See Fricks to Surgeon General, 19 August 1930, file 1850-95, "Rocky Moun- 
tain Spotted Fever Laboratory," box 158, "Domestic Stations, Hamilton, Mon- 
tana," PHS Records. Gordon E. Davis, who had just completed his D.Sc. 
degree in bacteriology at Johns Hopkins University and had spent time in 
Nigeria working with the Rockefeller Yellow Fever Commission, joined the 
laboratory as bacteriologist in October 1930. See RML, Monthly Report, 
October 1930. 

71. McCoy to Surgeon General, 11 April 1928, file i850,"Hamilton, Mon- 
tana," box 158, "Domestic Stations, Hamilton, Montana," PHS Records. 

Chapter Eight: Spotted Fever outside the Rockies 

1. Abstract of C. R. LaBier, "Rocky Mountain Spotted Fever in Indiana," 
]AMA 86 (i926):i50. 

2. John F. Anderson and Joseph Goldberger, "The Relation of So-called 
Brill's Disease to Typhus Fever," Pub. Health Rep. 27 (19 12): 149-60. The 
identification of Brill's disease and its use as a catchall diagnostic category 
were discussed in chap. 6. 

3. Kenneth F. Maxcy, "An Epidemiological Study of Endemic Typhus (Brill's 
Disease) in the Southeastern United States with Special Reference to Its Mode 
of Transmission," Pub. Health Rep. 41 (i926):2967— 95. For biographical 
information on Maxcy, see K. F. Meyer, "Presentation of Sedgwick Memorial 
Award to Dr. Maxcy for 1952," Am. J. Pub. Health 42 (19 5 2): 161 8-21; 
Barry, Notable Contributions (see chap. 5, n. 75), 52-54. Maxcy's study was 
apparently generated by questions raised when he presented a paper on "den- 
gue fever with a rash" at a Hygienic Laboratory review of staff research. 
Joseph Goldberger suggested that the symptoms sounded suspiciously like 
typhus fever. Maxcy thus held back a pending publication until he could do 
additional research, which confirmed the senior typhus investigator's view. As 
a result, Maxcy's publication contained not a description of atypical dengue 
fever but an authoritative study of endemic typhus. See Rolla Eugene Dyer, 
oral history interview by Harlan Phillips, 13 November 1962, p. 9, in George 
Rosen, Transcripts of Oral History Project, 1962—64, NLM (hereafter cited 
as Dyer oral history). 

4. R. D. Glasser, "Case of Typhus-Like Fever Following Tick Bite," Virginia 
Medical Monthly 56 (1930): 670— 71. 

5. Washington Post article cited in "Outbreak of Typhus Fever," JAMA 95 
(i93o):53; "Spread of Typhus Fever," /A MA 95 (i93o):207; "Conference on 
Typhus Fever," /AMA 95 (i93o):349; Robert Hickman Riley and Charles H. 
Halliday, Typhus, Spotted Fever in Maryland (Baltimore: Maryland State 
Department of Health, 1932). 

6. For biographical information on Dyer see Dyer oral history; Abel Wolman, 
"Sedgwick Memorial Medal to Dr. Dyer for 1950," Am. J. Pub. Health 40 
(i95o):i584-87; "Rolla Dyer Retires," JAMA 144 (i95o):248; and Barry, 
Notable Contributions, 19-22. 

7. Harden, Inventing the NIH (see chap. 3, n. 35), 50—159. 

8. Dyer oral history, 10; L. F. Badger, R. E. Dyer, and A. Rumreich, "An 
Infection of the Rocky Mountain Spotted Fever Type: Identification in the 
Eastern Part of the United States," Pub. Health Rep. 46 (i93i):463-70. 



Notes to Pages ijo-jj 



303 



9. A. Rumreich, R. E. Dyer, and L. F. Badger, "The Typhus-Rocky Mountain 
Spotted Fever Group: An Epidemiological and Clinical Study in the Eastern 
and Southeastern States," Pub. Health Rep. 46 (193 i):470-8o (quotations 
from pp. 470, 478); "Is Rocky Mountain Fever Present in the Eastern United 
States?" /i4MA 96 (i93i):ii46— 47 (quotation from p. 1147). 

10. Rumreich, Dyer, and Badger, "Typhus-Rocky Mountain Spotted Fever 
Group: Eastern and Southeastern States," 479; R. E. Dyer, L. F. Badger, and 
A. Rumreich, "Rocky Mountain Spotted Fever (Eastern Type): Transmission 
by the American Dog Tick [Dermacentor variabilis)^'' Pub. Health Rep. 46 
(193 1 ): 1403-13; L. F. Badger, "Rocky Mountain Spotted Fever (Eastern 
Type): Virus Recovered from the Dog Tick Dermacentor variabilis Found in 
Nature," Pub. Health Rep. 47 (i932):2365-69. 

11. Herman Mooser, M. Ruiz Castaneda, and Hans Zinsser, "Rats as Car- 
riers of Mexican Typhus Fever," JAMA 97 (i93i):23i— 32; R. E. Dyer, 
A. Rumreich, and L. F. Badger, "The Typhus-Rocky Mountain Spotted Fever 
Group in the United States," ibid., 589-94 (discussion, pp. 594-95). 

12. Ibid., 594. 

13. For a review^ of the status of typhus research in 1932, see R. E. Dyer, 
L. F. Badger, E. T Ceder, and W. G. Workman, "Endemic Typhus Fever of 
the United States: History, Epidemiology, and Mode of Transmission," JAMA 
99 (193 2): 79 5-80 1. I am grateful to Kimberly Pelis for copies of her tw^o 
untitled seminar papers, February and May 1988, Institute of the History of 
Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, 
which stimulated my thinking about the changing definition of tabardillo. 

14. M. H. Neill, "Experimental Typhus Fever in Guinea Pigs," Pub. Health 
Rep. 32 (i9i7):iio5-8; Herman Mooser, "Reaction of Guinea-Pigs to Mex- 
ican Typhus (Tabardillo): PreHminary Note on Bacteriologic Observations," 
JAMA 91 (i928):i9-2o; Herman Mooser, "Experiments Relating to the Pa- 
thology and the Etiology of Mexican Typhus (Tabardillo)," /. Inf. Dis. 43 
(i928):24i-72. 

15. Herman Mooser, "Essai sur I'histoire naturelle du typhus exanthema- 
tique," Archives de I'Institut Pasteur de Tunis 21 (i932):i-i9. In honor of 
Mooser's contribution to the knowledge of this disease, Brazilian investigator 
Jose Lemos Monteiro suggested that the rickettsiae of endemic typhus be called 
Rickettsia mooseri. See Jose Lemos Monteiro, "Estudos Sobre o Typho Ex- 
antematico de Sao Paulo," Memorias do Instituto Butantan 6 (i93i):i-i35 
(hereafter cited as Mem. Inst. Butantan). The name of the organism was later 
changed to Rickettsia typhi. 

16. Hans Zinsser, "Varieties of Typhus Virus and the Epidemiology of the 
American Form of European Typhus Fever (Brill's Disease)," Am. J. Hyg. 20 
(i934):5i3-32; E. S. Murray, G. Baehr, G. Schwartzman, R. A. Mandelbaum, 
N. Rosenthal, J. C. Doane, L. B. Weiss, S. Cohen, and J. C. Snyder, "Brill's 
Disease. I. Clinical and Laboratory Diagnosis," /AMA 142 (i95o):io59-66; 
E. S. Murray and J. C. Snyder, "Brill's Disease. II. Etiology," Am. J. Hyg. 53 
(i95i):22-32; John C. Snyder, "Typhus Fever Rickettsiae," in Horsfall and 
Tamm, eds.. Viral and Rickettsial Infections of Man, 4th ed. (see chap, i, n. 
7), 1078-87. 

17. William Fletcher, "Typhus-Like Fevers of Unknown y^^tiology, with 
Special Reference to the Malay States," Proc. R. Soc. Med. 23 (i93o):io2i- 
27 (discussion, pp. 1027-30; quotation from p. 1029). Fletcher noted the 
following local names for the typhus-like diseases: Rocky Mountain spotted 



Notes to Pages ij^-^j 



fever, endemic typhus, and Brill's disease in the United States; tick-typhus in 
India; urban tropical typhus, or shop typhus, and rural tropical typhus, or 
scrub typhus, in the Malay States; tropical typhus in Java and Sumatra; spo- 
radic typhus in French Indochina; endemic typhus and Mossman fever in 
Australia; fievre boutonneuse in North Africa; twelve-day fever in Nigeria; 
Brill's disease in South Africa; typhus-like fever in Kenya and Southern Rho- 
desia; fievre exanthematique and typhus endemique benin in the south of 
France; and febbre eruttiva in Italy. 

1 8. J. W. D. Megaw, "A Typhus-Like Fever in India, Possibly Transmitted 
by Ticks," Indian Med. Gaz. $6 {i9zi):}6i', idem, "Typhus Group of Fevers," 
ibid. 59 (1924): 169— 73; idem, "Indian Tick Typhus," ibid. 60 (1925): 5 8— 61. 

19. Fletcher, "Typhus-Like Fevers of Unknown i^ltiology," 1023. 

20. Ibid.; Charles NicoUe, "Unite ou pluralite des typhus exanthematiques," 
Bull. Soc. Path. Exot. 26 (i933):3i6— 40; Charles NicoUe, "Unite ou pluralite 
des typhus exanthematiques (A propos de la discussion de mon rapport a la 
seance du 9 fevrier)," Bull. Soc. Path. Exot. 26 (i933):375-76. 

21. "Small Epidemic of Mild Typhus," abstract in JAMA 89 (i927):705; 
"Exanthematic Typhus and Typhoid Infection with Exanthem" and "Epi- 
demics of Infectious Exanthems of Indeterminate Nature," abstracts in ibid. 
90 (i928):424; "Epidemic in Marseilles Due to Ticks," ibid. 95 (1930): 1846; 
Emile Brumpt, "Longevite du virus de la fievre boutonneuse {R. conori., n. 
sp.) chez la tique, Rhipicephalus sanguineus,"" Compt. rend. Soc. de biol. no 

(193 2) : 1 199-1202. Later taxonomic convention called for doubling the final 
/, hence this organism is known at present as R. conorii. 

22. Accounts of Brumpt's illness are in "Case of Rocky Mountain Spotted 
Fever in Paris," /AMA 100 (1933):! 190; RML, Monthly Report, March 1933; 
"Single Injection of Spotted Fever Serum Saves French Doctor," Helena [Mon- 
tana] Record, 15 April 1933, clipping in RML Scrapbook "1932-1940." 
JAMA reported that at the Hopital Pasteur, Brumpt received three doses of 
typhus serum, flown in from convalescents at the Pasteur Institute in Casa- 
blanca and at the hygienic institute in Warsaw. French parasitologist Jean 
Theodorides provided a slightly different version of Brumpt's therapy, told to 
him by a relative of Charles Nicolle. In this account, Nicolle advised Brumpt 
to be treated at the Hopital Pasteur, where Brumpt was cured by inoculation 
from his roommate, Paul Giroud, who was convalescing from a grave typhus 
infection, I am grateful to Dr. Theodorides for providing me with a preprint 
of the chapter on rickettsial diseases from his forthcoming book. 

23. "Case of Rocky Mountain Spotted Fever in Paris," 1 190; RML, Monthly 
Report, March 1933. 

24. L. F. Badger, "Rocky Mountain Spotted Fever and Boutonneuse Fever: 
A Study of Their Immunological Relationship," Pub. Health Rep. 48 

(193 3) : 507-11; Gordon E. Davis and R. R. Parker, "Comparative Experi- 
ments on Spotted Fever and Boutonneuse Fever (I)," ibid. 49 (i934):423-28. 

25. "A New Type of Typhus Fever," JAMA 96 (i93i):i968; "Typhus 
Epidemics in 1932," ibid. 100 (i933):i266; Robin L. Anderson, "Public 
Health and Public Healthiness, Sao Paulo, Brazil, 1 876-1 893," /. Hist. Med. 
Allied Sci. 41 (i986):293-307; George Browne, "Government Immigration 
in Imperial Brazil, 18 22-1 870," Ph.D. dissertation. Catholic University, 1972; 
Michael Hall, "The Origins of Mass Immigration in Brazil, 1871— 1914," Ph.D. 
dissertation, Columbia University, 1969. 



Notes to Pages 155-57 



305 



26. Ronald Hilton, in The Scientific Institutions of Latin America, with 
Special Reference to Their Organization and Information Facilities (Stanford: 
California Institute of International Studies, 1970), 564. 

27. "Experiments with Virus of Exanthematic Typhus," JAMA 97 
(i93i):262— 63. "Experiments with Virus of Typhus Fever," ibid., 1480 (quo- 
tation this article); Emmanuel Dias and Amilcar Vianna Martins, "Spotted 
Fever in Brazil: A Summary," Am. J. Trop. Med. 19 (1939): 103-8. See also 
Jose de Toledo Piza, Typho exantematico de Sao Paulo (Sao Paulo, Brazil: 
Sociedade Impressora PauHsta, 1932); J. Lemos Monteiro, "Estudos sobre o 
typho exantematico de Sao Paulo," Mem. Inst. Butantan 6 (193 1): 5-13; 
J. Lemos Monteiro, F. Fonseca, and A. Prado, "Pesquisas epidemiologicas 
sobre o typho exantematico de Sao Paulo," Mem. Inst. Butantan 6 (i93i):i39; 
J. Lemos Montiero, "Tentativos de transmissao experimental do 'typho ex- 
antematico' de Sao Paulo por percevejos [Cimex lenticularis)^'' Mem. Inst. 
Butantan 9 (1935):!; J. Lemos Monteiro and F. Fonseca, "Typho exantematico 
de Sao Paulo. XII. Sobre un virus isolado de ratos da zona urbana da cidade 
e suas relacoes com o do typho exantematico de Sao Paulo," Brasil Medico 
59 (1932): 137 (hereafter cited as Brasil Med.); J. Travassos, "Studies on 
Rickettsial Diseases in Brazil," in Carolyn Whitlock, ed.. Proceedings of the 
Fourth International Congresses on Tropical Medicine and Malaria, Wash- 
ington, D.C., May 10-18, 1948 (Washington, D.C.: Government Printing 
Office, 1948), 414-21 (discussion, pp. 421-25). 

28. R. R. Parker and Gordon E. Davis, "Protective Value of Convalescent 
Sera of Sao Paulo Exanthematic Typhus against Virus of Rocky Mountain 
Spotted Fever," Pub. Health Rep. 48 (i933):5oi-7; R. E. Dyer, "Relationship 
between Rocky Mountain Spotted Fever and 'Exanthematic Typhus of Sao 
Paulo,' " ibid., 521-22; R. R. Parker and Gordon E. Davis, "Further Studies 
on the Relationship of the Viruses of Rocky Mountain Spotted Fever and Sao 
Paulo Exanthematic Typhus," ibid., 839-43; Gordon E. Davis and R. R. 
Parker, "Additional Studies on the Relationship of the Viruses of Rocky Moun- 
tain Spotted Fever and Sao Paulo Exanthematic Typhus," ibid., 1006-11. 

29. RML, Monthly Report, January 1934, 2-3; RML, Annual Report, 19345 
2; "Tick Fever Serum Sent to Tropics," n.d., n.p., clipping in RML Scrapbook 
"1932-1940." 

30. RML, Monthly Report, February 1936, 8-9; list of spotted fever deaths 
from laboratory infections, "RMSF— Laboratory Infections— Book i," R. R. 
Parker Notebooks, RML Research Records; RML, Monthly Reports, April 
1937, 6; and May 1937, 12; "Brazil Doctors Leave Hamilton," Daily Mis- 
soulian, 19 May 1937; and "News Bits of Montanans," paper and date not 
cited, clippings in RML Scrapbook 2, "1932— 1940"; Travassos, "Studies on 
Rickettsial Diseases in Brazil," 418-19. 

31. L. Patino-Camargo, A. Afanador, and J. H. Paul, "A Spotted Fever in 
Tobia, Colombia: PreHminary Report," Am. J. Trop. Med. 17 (193 7): 639- 
53- 

32. Luis Patino-Camargo, "Neuvas observaciones sobre un tercer foco de 
fiebre petequial (maculosa) en el hemisferio americano," Boletin de la Oficina 
Sanitaria Panamerica 20 (1941):! 112-23 (hereafter cited as Bol. Offic. San. 
Panam.); RML, Annual Report, 1941, i- Calderon Cuervo's death in 1942 
is noted in Aristides A. Moll, Aesculapius in Latin America (Philadelphia: 
W. B. Saunders Co., 1944), 463; R. R. Parker, "RMSF— Laboratory Infec- 
tions—Book I," R. R. Parker Notebooks, RML Research Records. 



3o6 



Notes to Pages 157-59 



33. RML, Monthly Report, December 1941, 8. 

34. Badger, Dyer, and Rumreich, "An Infection," 466; Dyer, Badger, and 
Rumreich, "Rocky Mountain Spotted Fever: Transmission," 1403. 

35. Parker to G. W. McCoy, 21 July 193 1, RML, Monthly Report, July 
1931. 

36. Ibid. 

37. For biographical information on Lillie, see Frederick H. Kasten, "Ralph 
Dougall LiUie," in Clark and Kasten, History of Staining (see chap. 4, n. 51), 
1-34; G. G. Glenner, "Ralph D. Lillie: Pioneer in Three Specialties," Journal 
of Histochemistry and Cytochemistry 16 (i968):3-i6; J. D. Longley, "Ralph 
Dougall Lillie, 1896-1979," /. Histochem. Cytochem. 28 (i98o):29i-96; 
Frederick H. Kasten, "Ralph D. Lillie," Stain Technology 55 (i98o):2oi-i5; 
S. S. Spicer, "A Tribute to Dr. Ralph Dougall Lillie (i 896-1979)," Histo- 
chemical Journal 12 (i98o):495-98; "Ralph Dougall Lillie," in American Men 
and Women of Science^ 14th ed., ed. Jacques Cattell Press, Physical and Bi- 
ological Sciences, vol. 4 (New^ York: R. R. Bow^ker, 1979), 2991. 

38. Ralph D. Lillie, "Pathology of the Eastern Type of Rocky Mountain 
Spotted Fever," Pub. Health Rep. 46 (193 1): 2840-59 (quotations from p. 
2858). 

39. P. N. Harris, "Histological Study of a Case of the Eastern Type of Rocky 
Mountain Spotted Fever," American Journal of Pathology 7 (i933):9i— 104. 
M. C. Pincoffs and C, C. Shaw, "The Eastern Type of Rocky Mountain Spotted 
Fever: Report of a Case v^ith Demonstration of Rickettsiae," Medical Clinics 
of North America 16 (i933):io97-iii4; RalphD. Lillie, "Histologic Reaction 
to the Virus of Rocky Mountain Spotted Fever in Chick Embryos," Pub. Health 
Rep. 50 (i935):i498— 1501; Ralph D. Lillie and R. E. Dyer, "Brain Reaction 
in Guinea Pigs Infected w^ith Endemic Typhus, Epidemic (European) Typhus 
and Rocky Mountain Spotted Fever, Eastern and Western Types," Pub. Health 
Rep. 51 (i936):i293-i307. 

40. E. R. Maillard and E. L. Hazen, "Rocky Mountain Spotted Fever in 
New York State Outside of New York City," Am. J. Pub. Health 25 
(i935):ioi2-i7; Norman H. Topping and R. E. Dyer, "A Highly Virulent 
Strain of Rocky Mountain Spotted Fever Virus Isolated in the Eastern United 
States," Pub. Health Rep. 55 (i94o):728-3i; George D. Brigham and James 
Watt, "Highly Virulent Strains of Rocky Mountain Spotted Fever Virus Isolated 
from Ticks (D. variabilis) in Georgia," Pub. Health Rep. 55 (1940): 21 25-26; 
George D. Brigham and James Watt, "Additional Highly Virulent Strains of 
Rocky Mountain Spotted Fever Virus Isolated in Georgia," Pub. Health Rep. 
57 (1942): 1 342-44; Norman H. Topping, "A Strain of Rocky Mountain 
Spotted Fever Virus of Low Virulence Isolated in the Western United States," 
Pub. Health Rep. 56 (1941): 2041-43; Norman H. Topping, "Rocky Mountain 
Spotted Fever: A Note on Some Aspects of Its Epidemiology," Pub. Health 
Rep. 56 (i94i):i699-i703; Norman H. Topping, "The Epidemiology of 
Rocky Mountain Spotted Fever," New York State Journal of Medicine 47 
(i947):i585-87. 

41. Eugene P. Campbell and Walter H. Ketchum, "Rocky Mountain Spotted 
Fever: An Analysis of Seven Cases, Including One Laboratory Infection," New 
England Journal of Medicine 223 (1940): 540—43 (quotation from p. 540); 
Alfred L. Florman and Joseph Hafkenschiel, "The Eastern Variety of Rocky 
Mountain Spotted Fever: The Experience on the Adult Medical Service of The 



Notes to Pages 161-64 



307 



Johns Hopkins Hospital, Including the Report of a Fatal Case Showing Throm- 
bocytopenia," Bulletin of the Johns Hopkins Hospital 66 (1940): 123-3 3 (quo- 
tations from p. 132). 

42. Ralph D. Lillie, "Pathology of Rocky Mountain Spotted Fever. I. The 
Pathology of Rocky Mountain Spotted Fever. II. The Pathologic Histology of 
Rocky Mountain Spotted Fever in the Rhesus Monkey Macaca mulatta,'' U.S. 
National Institute of Health Bulletin no. 177 (1941), 53 pp. (quotations from 
pp. I, 27). 

43. "Epidemic in Marseilles Due to Ticks," JAMA 95 (i93o):i846; R. A. 
Cooley, "Preliminary Report on the Tick Parasite, Ixodiphagus caucurtei du 
Buysson," in MSBE, Seventh Biennial Report^ 17-31- 

44. C. P. Clausen, "Parasites and Predators," Yearbook of Agriculture 
(Washington, D.C.: Government Printing Office, 1952), 380—88; idem, "Bi- 
ological Control of Insect Pests in the Continental United States," U.S. De- 
partment of Agriculture Technical Bulletin no. 1139 (1956), 151 pp.; Marshall 
Hertig and David Smiley, Jr., "The Problem of Controlling Wood Ticks on 
Martha's Vineyard," Vineyard Gazette (Martha's Vineyard, Mass.), 15 Jan- 
uary 1937, clipping in RML Scrapbook "1935-1941"; Harvey L. Sweetman, 
The Principles of Biological Control: Interrelation of Hosts and Pests and 
Utilization in Regulation of Animal and Plant Populations (Dubuque, Iowa: 
WilUam C. Brown Co., 1958), 157. 

45. Cooley to Wolbach, 4 February 1928; and J. R. Parker to Wolbach, 17 
October 1928, vol. "Professors at Various Universities," CC. Several other 
volumes of the Cooley Correspondence also document Cooley's experiments 
with tick parasites. For published material see Cooley, "Tick Parasites— Ex- 
ecutive Report," in MSBE, Seventh Biennial Report^ 10-16; Fred A. Morton, 
"Quantity Production of Tick Parasites," MSBE, Seventh Biennial Report, 
32-35; J, R. Parker and W J. Butler, "Tick Parasite Liberation in Montana 
During 1928," MSBE, Seventh Biennial Report, 35-38. 

46. Application and correspondence, vol. "Tick Parasite Work— Africa, 
1928-1932," CC; Price, Fighting Spotted Fever (see chap. 3, n. 4), 208-11. 

47. RML, Monthly Report, May-June 1933. 

48. Ibid.; RML, Annual Report, 1933, 11— 13. 

49. RML, Monthly Reports, January 1934, 6-8; February 1935, 8-9; RML, 
Annual Report, 1934, 3. 

50. F. J. O'Donnell, "Control Work: Rocky Mountain Spotted Fever Control 
Districts, Bitter Root Valley, for the Biennium Ending December 31, 1932," 
in MSBE, Ninth Biennial Report, 7; RML, Monthly Reports, May 1935, 6, 
13-15; July 1935, 13-14; September 1935, 5; January 1936, 7; April 1936, 
4-5; RML, Annual Report, 1936, 13. 

51. Occasionally the press in other western states took politicians to task 
over the situation. One author reminded Idaho readers that although spotted 
fever had been "one of Idaho's most serious problems," the financial burden 
of battling the disease had been borne by Montana alone. "Thus Idaho gov- 
ernors" had been "spared the awkwardness of asking their legislatures for a 
few dollars to control a dread disease in this state." See H. H. Miller, "Battling 
a Dread Disease— Rocky Mountain Spotted Fever," Idaho Sunday Statesman 
(Boise), 5 April 1936, clipping in RML Scrapbook "1935-41." 

52. "Proposal to Surrender the Board's Research Work to the United States 
Government," in MSBE, Eighth Biennial Report, 13-14. 



3o8 



Notes to Pages 164-68 



53. "Rocky Mountain Spotted Fever Committee Report," n.d., folder 11, 
"Rocky Mountain Spotted Fever Committee, 1930," box i, "General Cor- 
respondence," MSBH Records; Hardy A. Kemp and C. M. Gribsby, "The 
Occurrence and Identification of an Infection of the Rocky Mountain Spotted 
Fever Type in Texas," Texas State Medical Journal 27 ( 193 1): 395-98. For the 
text of the resolution, see "Proposal to Surrender," 14-15. 

54. U.S. Congress, Senate, A Bill Authorizing the Purchase of the State 
Laboratory at Hamilton, Montana, Constructed for the Prevention, Eradi- 
cation, and Cure of Spotted Fever, S. 5959, 71st Cong., 3d sess., 26 January 
(calendar day 30 January) 193 1. Senator Walsh's speech, the discussion, and 
inserted letters are in U.S. Congress, Senate, Congressional Record, 71st Cong., 
3d sess., 30 January 1930, 3634-38. The identical bill was introduced by 
Congressman Scott Leavitt, 6 February 193 1, into the House of Representatives 
as H.R. 1 691 5. Copies of both bills and of correspondence about the bill 
circulated in the U.S. Public Health Service are in file 1960—62, "Hamilton- 
Spotted Fever," box 159, "Domestic Stations," PHS Records. 

55. U.S. Congress, Senate, Congressional Record, 71st Cong., 3d sess., 30 
January 1930, 3638. 

56. Correspondence and other records in file 1960-62, "Hamilton— Spotted 
Fever," box 159, "Domestic Stations," PHS Records; Price, Fighting Spotted 
Fever, 223—27; Harden, Inventing the NIH, 140-59; "Rocky Mountain Spot- 
ted Fever Committee Report," n.p. 

57. Parker to Surgeon General, telegram, 25 February 193 1; and Thompson 
to Parker, 3 March 193 1, file 1960-62, "Hamilton — Spotted Fever," box 159, 
"Domestic Stations," PHS Records; "Rocky Mountain Spotted Fever Com- 
mittee Report," n.p. 

58. The original draft erroneously authorized the Surgeon General of the 
U.S. Public Health Service to purchase the laboratory. This was revised, and 
the secretary of the Treasury was designated as the appropriate official. The 
second change was an addition stipulating that the laboratory would be ad- 
ministered and maintained as a part of the U.S. Public Health Service. See 
U.S. Congress, S. Rept. 1660 to Accompany S. 5959, 71st Cong., 3d sess., 17 
February 193 1. 

59. U.S. Congress, Senate, Congressional Record, 71st Cong., 3d sess., 20 
February 193 1, 5575-76; An Act Authorizing the Purchase of the State Lab- 
oratory at Hamilton, Montana, Constructed for the Prevention, Eradication, 
and Cure of Spotted Fever, 2 March 193 1, 46 Stat. L. 319; Second Deficiency 
Act, Fiscal Year 1931,4 March 1931, 46 Stat. L. 522. 

60. Spencer to Parker, 20 March 1932, file "Senior Surgeon R. R. Spencer," 
RML Director's Office files, Hamilton, Montana (hereafter cited as RML 
Director's Files). 

61. Budget projections and correspondence in file "Federal Government 
Reorganization — Recommendations of 1933," General Correspondence, 
Thomas Parran Papers, University Archives, University of Pittsburgh, Pitts- 
burgh (hereafter cited as Parran Papers); "Possible Cut in Funds for War 
Against Fever Menaces Hamilton Work," Daily Missoulian, 28 May 1933; 
"Dangerous Economy," Daily Missoulian, 29 May 1933; "Spotted Fever Re- 
search Fund May Be Slashed," Bozeman [Mont.] Chronicle, 28 May 1933; 
"Wood-Tick Fund May Be Reduced," Billings [Mont.] Gazette, 29 May 1933, 
clippings in RML Scrapbook "19 3 2-1 940." 



Notes to Pages i68-yo 



6z. Cumming to Ballantine, 17 April 1933, file "Federal Government Re- 
organization—Recommendations of 1933," General Correspondence, Parran 
Papers. 

63. "No Let-Up in Fight against Tick Fever," Cheyenne [Wyo.] Tribune, 4 
June 1933; "U.S. Will Continue Fight on Tick Fever," Denver [Colo.] Morning 
Post, 3 June 1933, clippings in RML Scrapbook "193 2-1940." 

64. Spencer to Parker, 5 July 1932, file "Senior Surgeon R. R. Spencer," 
RML Director's Files; Dedication, Fernald Club Yearbook, University of Mas- 
sachusetts, no. 19, January 1950, 2, NIAID files, NIH Historical Office; RML, 
Monthly Report, January— February 1933, 8-9. In 193 1, Parker also suffered 
the loss of his wife Adah Nicolet Parker, who had assisted him in his early 
career despite physical handicaps. They had two children. In 1932 Parker 
remarried, to Vivian Kaa, daughter of a prominent Hamilton surgeon. 

65. RML, Annual Reports, 1934, i; and 1936, 6-7. 

66. RML, Annual Report, 1933, 15—16; RML, Monthly Report, May 1934, 

2. 

67. R. R. Parker, "Tick-Borne Diseases of Man in Montana and Methods 
of Prevention," Montana State Department of Health Special Bulletin no. 47 
(1933), 12 pp.; RML, Monthly Report, March 1926, 9; Parker to Surgeon 
General, 17 July 193 1, letter bound with RML Monthly Reports. 

68. RML, Monthly Reports, August 1935, 9~io; March 1936, 3; RML, 
Annual Report, 1936, 8-10; G. E. Davis and H. R. Cox, "A Filter-Passing 
Infectious Agent Isolated from Ticks: I. Isolation from Dermacentor andersoni. 
Reactions in Animals, and Filtration Experiments," Pub. Health Rep. 53 
(i938):2259— 67; H. R. Cox, "Studies of a Filter-Passing Agent Isolated from 
Ticks. V. Further Attempts to Cultivate in Cell-Free Media. Suggested Clas- 
sification," Pub. Health Rep. 54 (i939):i822— 27. 

69. On contamination of the Spencer-Parker vaccine with Q fever organisms 
and the hypersensitivity reaction it produced, see Richard A. Ormsbee, inter- 
view by Victoria A. Harden, Hamilton, Montana, 2 August 1985 (hereafter 
cited as Ormsbee interview); David B. Lackman, E. John Bell, J. Frederick 
Bell, and Edgar G. Pickens, "Intradermal Sensitivity Testing in Man with a 
Purified Vaccine for Q Fever," Am. J. Pub. Health 52 (i962):87-93; J. Fred- 
erick Bell, David B. Lackman, Armon Meis, and W. J. Hadlow, "Recurrent 
Reaction at Site of Q Fever Vaccination in a Sensitized Person," Military 
Medicine 129 (1964): 591— 95. Robert N. Philip noted in a personal com- 
munication to the author, 16 February 1988, that the possibility of contam- 
ination was a major compelling factor in the search for a better method of 
spotted fever vaccine preparation. 

70. E. H. Derrick, " 'Q' Fever, a New Fever Entity: Clinical Features, Di- 
agnosis, and Laboratory Investigation," Medical Journal of Australia 2 

(1937) :28i-99; F. M. Burnet and M. Freeman, "Experimental Studies on the 
Virus of 'Q' Fever," ibid. 2 (193 7): 299-305; R. E. Dyer, "Filter-Passing In- 
fectious Agent Isolated from Ticks. Human Infection," Pub. Health Rep. 53 

(1938) :2277-82; R. E. Dyer, "Similarity of AustraHan 'Q' Fever and a Disease 
Caused by an Infectious Agent Isolated from Ticks in Montana," Pub. Health 
Rep. 54 (1939): 1229-37; H. R. Cox, ''Rickettsia diaporica and American Q 
Fever," Am. J. Trop. Med. 20 (i94o):463-69; F. M. Burnet and M. Freeman, 
"Studies of X Strain (Dyer) of Rickettsia burnetii-. Chorioallantoic Membrane 
Infections," /owm^z/ of Immunology 40 (i94i):405-i9; C. B. Philip, "Com- 



Notes to Pages lyo-yj 



ments on Name of Q Fever Organism," Pub. Health Rep. 63 (i948):58. For 
a recent historical account of the discovery of Q fever, see Jospeh E. McDade, 
"Historical Aspects of Q Fever," forthcoming. I am grateful to Dr. McDade 
for providing me with a preprint. 

71. Expansion of laboratory facilities, for example, had been authorized in 
193 1 by the appropriations act accompanying the purchase of the laboratory 
by the U.S. Public Health Service. Begun in April 1933, the new unit was 
designed specifically to separate vaccine production from other operations 
because of the hazards involved. The laboratory also benefited from New Deal 
expenditures under the Public Works Administration by the addition of officers' 
quarters and outbuildings. See RML, Annual Report, 1934. 

72. Ibid., 2. 

73. RML, Monthly Reports, December 1934, 3; April 1935, 3; and May 
1935? 35 Cumming to B. K. Wheeler, 19 July 1934, file 1975-85, "Hamilton- 
Spotted Fever Laboratory," box 159, "Domestic Stations," PHS Records. 

74. RML, Monthly Report, February 1934, 12-17; "Wood Tick Season Is 
Here: Residents Must Be Careful," Spokane [Wash.] Press, 19 March 1935, 
attached to RML, Monthly Report, March 1935, n.p.; letters in file 1975- 
85, "Hamilton— Spotted Fever Laboratory," box 159, "Domestic Stations," 
PHS Records. 

75. J. H. Rosenberg to Director, Spotted Fever Laboratory, 12 March 1934; 
and Mefford to Director, Spotted Fever Laboratory, 25 March 1934, attached 
to RML, Monthly Report, March 1934. 

76. RML, Monthly Report, March 1935, 4. 

77. Expressions of this philosophy are in Cooley to Cogswell, 28 November 
1927, vol. "W. F Cogswell, A. H. McCray, T D. Tuttle," CC; "U.S. Gov- 
ernment Spotted Fever Vaccine Available for Nevada Residents," Nevada 
Stockgrower, May 1929, 14, clipping in RML Scrapbook "19 19-19 31." 

78. Baker to Wheeler, 20 March 1935; and Parker to Surgeon General, 13 
April 1935, file 1975—85, "Hamilton— Spotted Fever Laboratory," box 159, 
"Domestic Stations," PHS Records; 1940s newspaper notices of free vaccine 
clinics in Ravalli County in RML Scrapbooks. 

79. RML, Monthly Report, March 1934. 

80. Thompson to Parker, 25 April 1934, file 1960—62, "Hamilton— Spotted 
Fever," box 159, "Domestic Stations," PHS Records. 

81. RML, Annual Report, 1933, 5. 

82. RML, Monthly Report, March 1935, 2; RML, Annual Reports, 1936, 
3; and 1937, 4. 

Chapter Nine: Dr. Cox's Versatile Egg 

1. Personal communications to the author. 

2. E. N. Wilmer, ed., Cells and Tissues in Culture: Methods, Biology and 
Physiology (New York: Academic Press, 1965), 1-17; A. M. Harvey, "Johns 
Hopkins— The Birthplace of Tissue Culture: The Story of Ross G. Harrison, 
Warren H. Lewis, and George O. Gey," Johns Hopkins Medical Journal 136 
(i975):i42-49; Frederick B. Bang, "History of Tissue Culture at Johns Hop- 
kins," Bull. Hist. Med. 51 (1977): 5 16-37. 

3. S. B. Wolbach and M. J. Schlesinger, "The Cultivation of the Microor- 
ganisms of Rocky Mountain Spotted Fever [Dermacentroxenus rickettsi) and 



Notes to Pages iy6-j8 



311 



of Typhus [Rickettsia prowazeki) in Tissue Plasma Cultures," /. Med. Res. 

44 (i9^3):2.3i-56. 

4. Alice Miles Woodruff and Ernest W. Goodpasture, "The Susceptibility 
of the Chorio-Allantoic Membrane of Chick Embryos to Infection with the 
Fowl-pox Virus," Am. J. Pathol. 7 (i93i):209-22. For a chronology of major 
papers on cultivation of other organisms by this method, see B. John Buddingh, 
"Chick-Embryo Technics," in Thomas M. Rivers, ed., Viral and Rickettsial 
Infections of Man ^ 2d ed. (Philadelphia: J. B. Lippincott Co., 1952), 109-25, 
esp. table 8, p. 110. 

5. For biographical information on Bengtson, see Barry, Notable Contri- 
butions (see chap. 5, n. 75), 9-12; "Ida Albertina Bengston [s/'c]," in Elizabeth 
Moot O'Hearn, Profiles of Pioneer Women Scientists (Washington, D.C.: 
Acropolis Books, 1985), 119-24; obituary by Alice C. Evans, Journal of the 
Washington Academy of Sciences 43 (i953):238-40. 

6. Ida A. Bengtson and R. E. Dyer, "Cultivation of the Virus of Rocky 
Mountain Spotted Fever in the Developing Chick Embryo," Pub. Health Rep. 
50 (193 5): 1489-98; Ralph D. Lillie, "Histologic Reaction to the Virus of 
Rocky Mountain Spotted Fever in Chick Embr^'os," ibid., 149 8-1 501. 

7. P. K. Olitsky and J. E. McCartney, "Experimental Studies on the Etiology 
of Typhus Fever. V. Survival of the Virus in Collodion Sacs Implanted Intra- 
Abdominally in Guinea Pigs," /. Exp. Med. 38 (i928):69i; Clara Nigg and 
Karl Landsteiner, "Studies on Cultivation of Typhus Fever Rickettsia in Pres- 
ence of Live Tissue," ibid. 55 (193 2) 15 63-76; Henry Pinkerton and G. M. 
Haas, "Spotted Fever. I. Intranuclear Rickettsiae in Spotted Fever Studied in 
Tissue Culture," ibid. 56 (i932):i5i— 56; Ida A. Bengtson, "Cultivation of 
the Rickettsiae of Rocky Mountain Spotted Fever in Vitro," Pub. Health Rep. 
52 (1937): 13 29-3 5; Ida A. Bengtson, "Immunizing Properties of Formolized 
Rocky Mountain Spotted Fever Rickettsiae Cultivated in Modified Maitland 
Media," Pub. Health Rep. 52 (i937):i696-i702 (quotation from p. 1702). 

8. An Act to Provide for the General Welfare by Establishing a System of 
Federal Old-Age Benefits, and by Enabling the Several States to Make More 
Adequate Provision for Aged Persons, Blind Persons, Dependent and Crippled 
Children, Maternal and Child Welfare, Public Health, and the Administration 
of Their Unemployment Compensation Laws; To Establish a Social Security 
Board; To Raise Revenue; and for Other Purposes, 14 August 1935, 49 Stat. 
L. 531. See esp. Title VI, "Public Health Work," 634-35. 

9. Attachment to Parker to Thompson, 21 March 1935, file 0425, "Ham- 
ilton—Spotted Fever Laboratory," box 159, "Domestic Stations," PHS Re- 
cords. 

10. Harden, Inventing the NIH (see chap. 3, n. 35), 170-73. 

11. RML, Monthly Report, February 1936, i. Officially, the date of this 
name change was recorded as 1937, when the NIH was reorganized. See 
National Institute of Allergy and Infectious Diseases, Intramural Contribu- 
tions, 1 8 87-1 9 8 7, ed. Harriet R. Greenwald and Victoria A. Harden (Bethesda, 
Md.: National Institute of Allergy and Infectious Diseases, 1987), 4 (hereafter 
cited as NIAID, Intramural Contributions, i88y-i^8j). 

12. For biographical information on Cox, see "Herald R. Cox," American 
Men and Women of Science, i6th ed., ed. Jacques Cattell Press, Physical and 
Biological Sciences, vol. 2 (New York: R. R. Bowker, 1986), 414; "Herald 
R. Cox," World Who's Who in Science: A Biographical Dictionary of Notable 



312 



Notes to Pages 



Scientists from Antiquity to the Present, ed. Allen G. Debus (Chicago: Marquis- 
Who's Who, 1968), 381; "Noted Researcher Dies in Hamilton," Daily Mis- 
soulian, 19 August 1986, 6. Cox died 17 August 1986. 

13. The virologist was Thomas Rivers, cited in Benison, Tom Rivers (see 
chap. 6, n. 56), 251—52; RML, Monthly Reports, May 1936, 13; and June 
1936, 10. 

14. H. R. Cox, "Reminiscences," in Willy Burgdorfer and Robert L. Anacker, 
eds., Rickettsiae and Rickettsial Diseases (New York: Academic Press, 1981), 
11-15 (quotations from pp. 11— 12). 

15. Ibid., 13. When Cox made this discovery, the identity of Nine Mile 
fever and Q fever had not been established. 

16. H. R. Cox, "Use of Yolk Sac of Developing Chick Embryo as Medium 
for Growing Rickettsiae of Rocky Mountain Spotted Fever and Typhus 
Groups," Pub. Health Rep. 53 (i938):224i-47; idem, "Rocky Mountain 
Spotted Fever: Protective Value for Guinea Pigs of Vaccine Prepared from 
Rickettsiae Cultivated in Embryonic Chick Tissues," ibid. 54 (i939):i070— 
77; H. R. Cox and E. John Bell, "The Cultivation of Rickettsia diaporica in 
Tissue Culture and in the Tissues of Developing Chick Embryos," ibid., 21 71- 
78; H. R. Cox and E. John Bell, "Epidemic and Endemic Typhus: Protective 
Value for Guinea Pigs of Vaccines Prepared from Infected Tissues of the 
Developing Chick Embryo," ibid. 55 (i94o):iio— 15; H. R. Cox, "Cultivation 
of Rickettsiae of the Rocky Mountain Spotted Fever, Typhus, and Q Fever 
Groups in the Embryonic Tissues of Developing Chicks," Science 94 
(i94i):399-403 (quotation from p. 401). 

17. Hans Zinsser, Florence K. Fitzpatrick, and Hsi Wei, "A Study of Rick- 
ettsiae Grown on Agar-Tissue Cultures," /. Exp. Med. 69 (1939): 179-90; 
Florence K. Fitzpatrick, "Vaccination against Spotted Fever with Agar-Tissue 
Cultures," Proceedings of the Society for Experimental Biology and Medicine 
42 (i939):2i9-20. 

18. RML, Annual Report, 1939, i; Cox, "Rocky Mountain Spotted Fever: 
Protective Value for Guinea Pigs," 1070-77; Timothy J. Kurotchkin and Ralph 
W. G. Wycoff, "Immunizing Value of Rickettsial Vaccines," Proc. Soc. Exp. 
Biol. Med. 46 (i94i):223— 28. 

19. RML, Annual Report, 1940, 1-2; J. D. RatcHff, "Bite of Death," Collier's, 
28 March 1942, 15, 42-43. 

20. "U.S. Public Health Service Orientation Course for Personnel to Serve 
in Health and Sanitation Activities in Connection with National Defense," 
Pub. Health Rep. 56 (1941): 662-63. 

21. Hartwin A. Schulze, "Typhus on the Western Front in World War II," 
Military Surgeon loi (i947):489-98 (quotation from p. 490). 

22. For biographical information on Topping, see Norman Topping, oral 
history interview by Harlan Phillips, 24 April 1964, in George Rosen, Tran- 
scripts of Oral History Project, 1962-64, NLM (hereafter cited as Topping 
oral history); American Men of Science, iith ed., ed. Jacques Cattell Press, 
Physical and Biological Sciences, vol. St-Z (New York: R. R. Bowker Co., 
i9^7)» 5441; Norman Topping, with Gordon Cohn, Recollections (Los An- 
geles: University of Southern California, 1990). I am grateful to Dr. Topping 
and to Mr. Cohn for making available a copy of this book in manuscript. 

23. Eugene P. Campbell and Walter H. Ketchum, "Rocky Mountain Spotted 
Fever: An Analysis of Seven Cases, Including One Laboratory Infection," New 



Notes to Pages 184-8J 



313 



England J. Med. 223 (i94o):540-43 (Topping's case is discussed on p. 540). 
Dr. Campbell kindly provided me with a copy of his personal records of 
Topping's illness. 

24. Rudolf Weigl, "Untersuchungen und Experimente an Fleckfieberlausen. 
Die Technik der Rickettsia-Forschung," Beitrdge zur Klinik der Infektion- 
skrankheiten und zer Immunitatsforschung 8 (i92o):3 53-76; idem, "Die 
Methoden der aktiven Fleckfieber-Immunisierung," Bulletin International de 
VAcademie Polonaise des Sciences et des Lettres, Classe de Medecine, July 
1930, 25—62; Peter K. Olitsky, "Hans Zinsser and His Studies on Typhus 
Fever," JAMA 116 (i94i):907— 12 (Weigl's vaccine is discussed on pp. 909, 
911). 

25. Hans Zinsser and M. Ruiz Castaneda, "Studies on Typhus Fever. V. 
Active Immunization against Typhus Fever with Formalinized Virus," /. Exp. 
Med. 53 (i93i):325-3i; idem, "A Note of Improvement in the Method of 
Vaccine Production with Rickettsiae of Mexican Typhus Fever," /. Immunol. 
21 (193 1 ) 1403-7; idem, "A Method of Obtaining Large Amounts of Rickettsia 
provaceki [sic] by X-ray Radiation of Rats," Proc. Soc. Exp. Biol. Med. 29 
(19 3 2): 840— 44; idem, "Studies on Typhus Fever. IX. On the Serum Reaction 
of Mexican and European Typhus Rickettsia," /. Exp. Med. 56 ( 193 2) -.455- 
67; M. Ruiz Castaneda, "Experimental Pneumonia Produced by Typhus Rick- 
ettsiae," Am. J. Pathol. 15 (i939):467-76. 

26. Paul Durand and Paul Giroud, "Essais de vaccination contre le typhus 
historique au moyen de rickettsias tuees par le formol (souches pulmonaires)," 
Compt. rend. Acad. d. sc. 210 (i94o):493— 96; Norman H. Topping and 
Charles C. Shepard, "The Rickettsiae," in Annual Review of Microbiology i 
(i947):333-50 (quotation from p. 334). 

27. James Craigie, "Application and Control of Ethyl-Ether- Water Interface 
Effects to the Separation of Rickettsiae from Yolk Sac Suspensions," Canadian 
Journal of Research 23 (1945): 104— 14. Because of wartime censorship, Crai- 
gie's method was submitted in 1942 to the Associate Committee on Medical 
Research of the National Research Council of Canada, which had supported 
the work financially, as a confidential document for restricted distribution in 
mimeographed form. It was not published openly until January 1945. 

28. E. John Bell, interview by Victoria A. Harden, Hamilton, Montana, 5 
August 1985, 4, NIAID files, NIH Historical Office; Norman H. Topping, 
Ida A. Bengtson, and M. J. Shear, "Studies of Typhus Fever Vaccines," in 
"Studies of Typhus Fever," U.S. National Institute of Health Bulletin no. 183 
(1945): 1—24; Ida A. Bengtson, Norman H. Topping, and Richard G. Hen- 
derson, "Epidemic Typhus: Demonstration of a Substance Lethal for Mice in 
the Yolk Sac of Eggs Infected with Rickettsia prowazeki,'' U.S. National In- 
stitute of Health Bulletin no. 183 (1945) 125-29; Richard G. Henderson, 
"Notes on the Mouse Test with Typhus Vaccine," U.S. National Institute of 
Health Bulletin no. 183 (i945):33— 35; Harry Plotz, Report on Contributions 
from the Division of Virus and Rickettsial Diseases, Army Medical School, 
on the Development of the Typhus Vaccine, 18 January 1946. In 1940 toxic 
activity associated with the organism of murine typhus had been demonstrated, 
and subsequently it was discovered in yolk sac tissue infected with spotted 
fever and boutonneuse fever. See E. Gildemeister and E. Haagen, "Fleckfie- 
berstudien. I. Mitteilung: Nachweis eines Toxins in Rickettsien-Eikulturen 
{Rickettsia mooseri),'' Deutsche med. Wchnschr. 66 (i94o):878-8o. Eng. 



314 



Notes to Pages i8j-8y 



trans, in Hahon, Selected Papers (see chap. 6, n. 26), 213-20; J. E. Smadel, 
E. B. Jackson, B. L. Bennett, and F. L. Rights, "A Toxic Substance Associated 
with the GilUam Strain of R. orientalis,'' Proc. Soc. Exp. Biol. Med. 62 
(1964): 1 3 8-40; E. J. Bell and E. G. Pickens, "A Toxic Substance Associated 
with the Rickettsias of the Spotted Fever Group,"/. Immunol. 70 (i953):46i- 
72.. 

29. Norman H. Topping, "Notes on the Preparation of Epidemic Typhus 
Vaccine," 30—32. In a personal communication to the author, 2 September 
1988, Norman H. Topping commented that by the time the vaccine was in 
production, "it had been so modified by Craigie and by us at the NIH that 
other than the hen's egg it had no resemblance to that described by Cox." 

30. "Bolivia Experimenting with Dr. Herold [sic] Cox' Vaccine, May Save 
Millions of Lives," Missoula Sentinel., 4 September 1941, clipping in RML 
Scrapbook "1941-1942"; Topping "Recollections." 

31. "Active Immunization against Typhus," JAMA 119 (i942):50o— 501; 
Ratcliff, "Bite of Death," 43. 

32. RML, Monthly Reports, February 1942, 3; and March 1942, i; "Im- 
munization and Multiple Antigens," /AMA 128 (i945):6i3; "Eyes of Nation 
on Typhus Lab," Spokesman Review (Spokane, Wash.), 29 March 1942, 
clipping in RML Scrapbook "1942- "; Ratcliff, "Bite of Death," i5ff.; 
J. Kobler, "Blitz Plague: Will Typhus Shape the Course of War?" Saturday 
Evening Post 215 (22 August i942):26ff. George D. Brigham, a Yale-trained 
bacteriologist, assumed Cox's post as head of the RML's typhus unit. See 
"Typhus Expert to Valley Lab from Southland," Daily Missoulian., 29 No- 
vember 1942, clipping in RML Scrapbook "1941— 1942." 

33. Production of yellow fever vaccine at the RML came about somewhat 
by chance. Before the war the U.S. Public Health Service had sent Mason V. 
Hargett, an officer trained in tropical diseases, to the Rockefeller Foundation 
headquarters in Brazil in order to learn methods of vaccine production that, 
it was hoped, would allow the Service to manufacture a limited amount for 
its own use. In October 1940, Hargett estabHshed a vaccine production unit 
with his assistant, Harry Burruss, at the RML — a site chosen because of the 
absence of Aedes egypti mosquitoes. Hargett's research convinced him that 
the vaccine could be improved by removing the human serum added as a 
stabilizer, and he subsequently developed an "aqueous-base" vaccine. After a 
1942 outbreak of jaundice among military personnel that was traced to con- 
taminated serum used in the Rockefeller Foundation's yellow fever vaccine, 
the U.S. military requested that Hargett produce all subsequent yellow fever 
vaccine using his modified method. See M. V. Hargett, H. W. Burruss, and 
A. Donovan, "Aqueous Base Yellow Fever Vaccine," Pub. Health Rep. 58 
(1943): 505-12; Mason V. Hargett, interview by Victoria A. Harden, Ham- 
ilton, Montana, 2 August 1985; and Harry Burruss, interview by Harden, 
Gaithersburg, Maryland, 17 April 1986, NIAID files, NIH Historical Office 
(copies also in NLM). 

34. RML, Monthly Report, December 1941, 9-10. 

35. Glen M. Kohls, "Rocky Mountain Spotted Fever," in Medical Depart- 
ment, U.S. Army, Preventive Medicine in World War II, vol. 7, Communicable 
Diseases: Arthropodborne Diseases Other Than Malaria (Washington, D.C.: 
Government Printing Office, 1964), 349—56. 



Notes to Pages i88~po 



315 



36. "Workman's Compensation Acts: Death from Rocky Mountain Spotted 
Fever Caused by Bite of Wood Tick Allegedly Received in Course of Em- 
ployment," /AMA 121 (i943):i49-50. 

37. Executive Order no. 9285, "Establishing the United States of America 
Typhus Commission," Federal Register 7 (no. 253, December 1942): 10899; 
Stanhope Bayne-Jones oral history memoir (Harlan Phillips, interview^er), 5 
vols., NLM, 3:641-46 (quotation from p. 644) (hereafter cited as Bayne-Jones 
oral history); Stanhope Bayne-Jones, "The United States of America Typhus 
Commission," Army Medical Bulletin 68 (i943):4-i5; Stanhope Bayne-Jones, 
"Typhus Fevers," in Medical Department, U.S. Army, Preventive Medicine in 
World War II, vol. 7, Communicable Diseases: Arthropodborne Diseases 
Other Than Malaria, 175—274. 

38. Material from the journal and personal files of Eugene P. Campbell, 
Chevy Chase, Maryland. Included in this material is the draft of an oral history 
prepared by Campbell with his colleague at the Institute of Inter-American 
Affairs, James Williams, v^hich w^ill be placed in the Columbia University oral 
history collection With other institute materials. Campbell also noted that the 
reference work on typhus in Guatemala used by the U.S. physicians was George 

C. Shattuck, A Medical Survey of the Republic of Guatemala (Washington, 

D. C.: Carnegie Institution of Washington, 1938), which cited Hans Zinsser 
on "Mexican typhus." This again reflects how misleading the phrase Mexican 
typhus had become, implying that typhus in Mexico was exclusively murine. 

39. Topping oral history, 10; Bayne-Jones oral history, 653; Arthur P. Long, 
"The Army Immunization Program," in Medical Department, U.S. Army, 
Preventive Medicine in World War II, vol. 3, Personal Health Measures and 
Immunization (Washington, D.C.: Government Printing Office, 1955), 2.71— 
72, 319—23; Bayne-Jones, "Typhus Fevers," 238-39. 

40. Bayne-Jones, "Typhus Fevers," table 3 3 , p. 180. Many other pubHcations 
refer to 64 as the total number of typhus cases during the war, citing Joseph 
F. Sadusk, Jr., "Typhus Fever in the United States Army Following Immuni- 
zation," /AMA 133 (i947):ii92-99. Bayne-Jones notes that his figure of 104 
cases was based on data revised through October i960. 

41. C. H. Stuart-Harris, "Discussion on the Control of Rickettsial Infec- 
tions," Proc. R. Soc. Med. 38 (i945):5ii— 18; A. Sachs, "Typhus Fever in 
Iran and Iraq, 1942-43: A Report on 2,859 Cases," /. Royal Army Med. 
Corps 86 (i946):87-io8; A. G. Gilliam, "Efficacy of Cox-Type Vaccine in 
the Prevention of Naturally Acquired Louse-Borne Typhus Fever," Am. J. Hyg. 
44 (i946):40i— 10; Herman Gold and Florence K. Fitzpatrick, "Typhus Fever 
in a Previously Vaccinated Laboratory Worker," JAMA 119 (i942):i4i5-i7; 
N. H. Topping, "Typhus Fever: A Note of the Severity of the Disease among 
Unvaccinated and Vaccinated Laboratory Personnel at the National Institute 
of Health," Am. J. Trop. Med. 24 (1944): 57-62; R. S. Ecke, A, G. Gilliam, 
J. C. Snyder, Andrew Yeomans, C. J. Zarafonetis, and E. S. Murray, "The 
Effect of Cox-Type Vaccine on Louse-Borne Typhus Fever: An Account of 61 
Cases of Naturally Occurring Typhus Fever in Patients Who Had Previously 
Received One or More Injections of Cox-Type Vaccine," Am. J. Trop. Med. 
25 (i945):447-62. 

42. H. L. Haller and S. J. Cristol, "The Development of New Insecticides," 
in Advances in Military Medicine (Boston: Little, Brown & Co., 1948), 2:621- 



3i6 



Notes to Pages ipi—pj 



26; William A. Hardenbergh, "Control of Insects," and "The Research Back- 
ground of Insect and Rodent Control," in Medical Department, U.S. Army, 
Preventive Medicine in World War II, vol. 2, Environmental Hygiene (Wash- 
ington, D.C.: Government Printing Office, 1955), 231-32, 251-69. For a 
personal account of this work and remarks about the Audubon Society's 
w^arning, see Ormsbee interview (see chap. 8, n. 69), 11— 12. 

43. Bayne-Jones oral history, 649-50; Schulze, "Typhus on the Western 
Front m World War II," 491. 

44. "Typhus in Naples," Rockefeller Foundation Review (1944) 13 3-3 6 
(quotation from p. 35). See also Charles M. Wheeler, "Control of Typhus in 
Italy 1943-1944 by Use of DDT," Am. J. Pub. Health 36 (1946): 119-29; 
Bayne-Jones, "Typhus Fevers," 217—31. 

45. These events were discussed in chap. 8. 

46. F. L. Kelly, "Weil-Felix Reaction in Rocky Mountain Spotted Fever," 
/. Inf. Dis. 32 (i923):223-25; A. L. Kerlee and R. R. Spencer, "Rocky Moun- 
tain Spotted Fever: A Preliminary Report on the Weil-Felix Reaction," Pub. 
Health Rep. 44 (1929): 179-82. The development of the Weil-Felix reaction 
was discussed in chap. 6. 

47. R. R. Spencer and K. F. Maxcy, "The Weil-Felix Reaction in Endemic 
Typhus Fever and in Rocky Mountain Spotted Fever," Pub. Health Rep. 45 
(i93o):440-46. 

48. "Weil-Felix Reaction in Typhus Fever," abstract in JAMA 90 (i928):33i. 
Kenneth F. Maxcy, however, noted that rabbits inoculated with a patient's 
blood early in the illness could later be tested for the development of Weil- 
Felix agglutinins. Not only would this procedure confirm the diagnosis if the 
patient died, but it was also useful for small laboratories that lacked facilities 
to maintain large supplies of guinea pigs for protection tests or direct isolation 
of the organism. K. F. Maxcy, "The Weil-Felix Reaction of the Rabbit in the 
Diagnosis of Rocky Mountain Spotted Fever (Eastern Type)," /. Inf. Dis. 58 
(i936):288-92. 

49. Spencer and Maxcy, "The Weil-Felix Reaction," 441. 

50. L. F. Badger, "Laboratory Diagnosis of Endemic Typhus and Rocky 
Mountain Spotted Fever," Am. J. Pub. Health 23 (193 3): 19— 27; idem, "The 
Laboratory Diagnosis of Endemic Typhus and Rocky Mountain Spotted Fever 
with Special Reference to Cross-Immunity Tests," Am. J. Trop. Med. 13 
(i933):i79-90 (quotation from p. 179). 

51. Henry Pinkerton and George M. Hass, "Spotted Fever. I. Intranuclear 
Rickettsiae in Spotted Fever Studied in Tissue Culture," /. Exp. Med. 56 
(i932):i5i-56; idem, "Spotted Fever. III. The Identification of Dermacen- 
troxenus rickettsi and Its Differentiation from Non-Pathogenic Rickettsiae in 
Ticks," ibid. 66 (i937):729— 39. 

52. Jules Bordet and Octave Gengou, "Sur I'existence de substances sen- 
sibilisatrices dans la plupart des serum antimicrobiens," Annales de I'Institut 
Pasteur 15 (1901): 289-302; Bordet, "Sur la mode d'action des serums cy- 
tolytiques et sur I'unite de I'alexine dans un meme serum," ibid. 303-18; 
Debra Jan Bibel, Milestones in Immunology: A Historical Exploration (Mad- 
ison, Wis.: Science Tech Publishers, 1988), 268-71. 

53. Benjamin F. Davis and William F. Petersen, "Complement Deviation in 
Rocky Mountain Spotted Fever,"/. Inf. Dis. 8 (i9ii):330-38; idem, "Unfin- 
ished Experiments of Dr. Howard T. Ricketts on Rocky Mountain Spotted 



Notes to Pages 194-^^ 



317 



Fever," in Ricketts, Contributions to Medical Science (see chap. 4, n. 10), 
409-18. 

54. See citations to this work in Ida A. Bengtson and Norman H. Topping, 
"Complement-Fixation in Rickettsial Diseases," Am. J. Pub. Health 32 
(i942):48-58, esp. the bibliography, p. 58. 

55. M. Ruiz Castaneda, "Studies on the Mechanism in Typhus Fever; Com- 
plement-Fixation in Typhus Fever," /. Immunol. 31 (19 3 6): 28 5-91. 

56. Other types of diagnostic tests were also investigated, several of which 
will be discussed in chap, 11. In one of the earliest of these studies, Florence 
K. Fitzpatrick and Bettylee Hampil, researchers at the Sharp and Dohme 
pharmaceutical house, reported that antibodies in rabbits inoculated with 
typhus and spotted fever antigens appeared earlier and persisted longer than 
did antibodies to B. proteus. More importantly, the sequence of appearance 
of the antibodies was always the same. See Florence K. Fitzpatrick and Bettylee 
Hampil, "Immunological Reactions in Rickettsial Diseases with Special Ref- 
erence to the Time of Appearance of Antibodies," Am. J. Pub. Health 31 
(i94i):i30i-5. 

57. Bengtson and Topping, "Complement-Fixation in Rickettsial Diseases," 
49; Ida A. Bengtson, "Applications of Complement-Fixation Test in Study of 
Rickettsial Diseases," Am. J. Pub. Health 35 (1945): 701-7. Recent advances 
in immunology help to explain the differences between the Weil-Felix and the 
complement fixation tests. Weil-Felix antibodies are of the IgM class, which 
provide one of the earliest responses of the body to invasion by foreign or- 
ganisms. These antibodies, however, do not persist for long periods of time. 
This may explain why the Weil-Felix test provided an earlier indication of 
rickettsial infection in a higher percentage of cases tested by Bengtson and 
Topping. Moreover, in the case of Brill's disease, IgM antibodies are not 
reformulated during recrudescence of the epidemic typhus infection. Because 
of this, a fourfold rise in Weil-Felix titer may be used to identify a new infection 
with R. prowazeki and to rule out Brill's disease. 

The complement fixation text, in contrast, responds more efficiently to 
antibodies of the IgG class. These antibodies appear later than do IgM anti- 
bodies, but they persist longer, which explains why the complement fixation 
reaction responded over a longer period of time than did the Weil-Felix. See 
R. N. Philip, C. A. Casper, J. N. McCormack, D. J. Sexton, L. A. Thomas, 
R. L. Anacker, W. Burgdorfer, and S. Vick, "A Comparison of Serologic 
Methods for Diagnosis of Rocky Mountain Spotted Fever," American journal 
of Epidemiology 105 (i977):56-67. 

58. Harry Plotz and Kenneth Wertman, "The Use of the Complement Fix- 
ation Test in Rocky Mountain Spotted Fever," Science 95 ( 1942) :44 1-42; 
Harry Plotz, K. Wertman, and B. L. Bennett, "Identification of Rickettsial 
Agents Isolated in Guinea Pigs by Means of Specific Complement Fixation," 
Proc. Soc. Exp. Biol. Med. 61 (i946):76-8i. 

59. Joseph E. Smadel, "The Practitioner and the Virus Diagnostic Labo- 
ratory," /AMA 136 (i948):i079-8i (quotation from p. 1080). 

60. David B. Lackman, interview by Victoria A. Harden, Helena, Montana, 
12 August 1985, lo-ii, NIAID files, NIH Historical Office; James van der 
Scheer, Emil Bohnel, and Herald R. Cox, "Diagnostic Antigens for Epidemic 
Typhus, Murine Typhus and Rocky Mountain Spotted Fever," /. Immunol. 
56 (i947):365-75. 



3i8 



Notes to Pages 196—^8 



61. Berton Roueche, "The Alerting of Mr. Pomeranz," New Yorker, 30 
August 1947, 28ff; Robert J. Huebner, P. Stamps, and Charles Armstrong, 
"Rickettsialpox— A Newly Recognized Rickettsial Disease. I. Isolation of the 
Etiological Agent," Pub. Health Rep. 61 (1946): 1605-14; Morris Greenberg, 
Ottavio Pellitteri, Irving F. Klein, and Robert J. Huebner, "Rickettsialpox— 
A Newly Recognized Rickettsial Disease. II. Clinical Observations," JAMA 
133 (i947):90i-6; Morris Greenberg, Ottavio Pellitteri, and William L. 
Jellison, "Rickettsialpox— A Newly Recognized Rickettsial Disease. III. Epi- 
demiology," Am. J. Pub. Health 37 (i947):86o-68; Robert J. Huebner, Wil- 
liam L. Jellison, and Charles Pomerantz, "Rickettsialpox— A Newly Recog- 
nized Rickettsial Disease. IV. Isolation of a Rickettsia Apparently Identical 
with the Causative Agent of Rickettsialpox from Allodermanyssus sanguineus., 
a Rodent Mite," Pub. Health Rep. 61 (i946):i677-82; Robert J. Huebner, 
William L. Jellison, and Charles Armstrong, "Rickettsialpox— A Newly Rec- 
ognized Rickettsial Disease. V. Recovery of Rickettsia akari from a House 
Mouse [Mus musculus),"" Pub. Health Rep. 61 (i947):777-8o; H. M. Rose, 
"The Clinical Manifestations and Laboratory Diagnosis of Rickettsialpox," 
Annals of Internal Medicine }i (i949):87i-83; L. N. Sussman, "Kew Gardens' 
Spotted Fever," New York Medicine 1 (i946):27-28; "Rickettsialpox: A New 
Rickettsial Disease," JAMA 137 (i948):384-85. For a later review of rick- 
ettsialpox, see David B. Lackman, "A Review of Information on Rickettsialpox 
in the United States," Clinical Pediatrics 2 (1963) 1296— 301. 

62. J. C. Woodland, M. M. McDowell, and J. T. Richards, "BuUis Fever 
(Lone Star Fever— Tick Fever)," /AMA 122 (1943): 11 56-60; "The Rickettsial 
Etiology of BulHs Fever," ibid. 124 (i944):926; William L. Jellison, interview 
by Victoria A. Harden, Hamilton, Montana, 3 August 1985, NIAID files, NIH 
Historical Office. In a personal communication to the author, 12 February 
1988, David B. Lackman observed that clinical findings among patients as 
well as tests made at the RML indicated that Bullis fever was really Q fever. 
Other investigators disagreed, however, and the issue was never settled. 

Chapter Ten: Spotted Fever Therapy, 
from Sage Tea to Tetracycline 

1. William Osier, "Teaching and Thinking: The Two Functions of a Medical 
School,'" Montreal Medical Journal 23 (1895): 5 61-72 (quotation from p. 568). 

2. Contrast this with the social, political, and medical response to cholera 
in the nineteenth century. See Charles E. Rosenberg, The Cholera Years: The 
United States in 18^1, 1849, and j ^6^^ (Chicago: University of Chicago Press, 
1962). 

3. The people of the Bitterroot, for example, pressed early investigators for 
some medical treatment for the disease and, as pointed out in chap. 4, welcomed 
Howard Taylor Ricketts's experimental antiserum. In 191 1, Thomas B. 
McClintic also noted the fervor for an effective therapy. "From the view point 
of the inhabitants of the Bitter Root Valley, the treatment of spotted fever 
ranks in importance second only to the eradication of the disease. Their desire 
is for a remedy with which human cases of the disease may be successfully 
treated." See McClintic, "Investigations and Tick Eradication," 747, cited in 
chap. 5, n. 33. 

4. McClintic, "Investigations and Tick Eradication," 748. 



Notes to Pages 1^8-202 



319 



5. Ibid., 747-54 (quotations from p. 754). 

6. Wolbach to Chairmen of the State Boards of Entomology and Heahh, 
18 January 19 18, vol. "Professors at Various Universities," CC; R. R. Spencer, 
"Annual Report of Rocky Mountain Spotted Fever Investigations," [1923], 
file 1266, box 119, Central File, 1897-1923, PHS Records. 

7. H. P. Greeley, "Mercurochrome-220 Soluble in Rocky Mountain Spotted 
Fever," JAMA 83 (1924): 1506-7. 

8. Parker to Robert A. Cooley, 11 April 1926; and Cooley to Parker, 16 
April 1926, vol. "R. R. Parker, 1926-193 1," CC; L. C. Fisher, "Chemotherapy 
of Experimental Spotted Fever," Proc. Soc. Exp. Biol. Med. 29 (i932):633- 
35 (quotations from pp. 633-34). Laboratory research on spotted fever oc- 
casionally produced a bizarre episode that seemed to stand common sense on 
its head. In the late 1920s it was discovered that an induced fever had a 
beneficial effect on the course of syphilis, and therapeutically infecting syphilis 
patients with malaria was popular for a period. Rocky Mountain spotted fever, 
of course, similarly produced a high fever. Exploiting this line of research, 
European researchers inoculated rabbits with both syphilis and spotted fever. 
They reported that the temperature rise resulting from this spotted fever "ther- 
apy" for syphilis "exerted a curative influence on the syphilitic infection." 
There is no evidence, however, that virulent spotted fever was ever employed 
in treating human victims of syphilis. See "Fever Treatment of Experimental 
SyphiHs," abstract in JAMA 89 (i927):4i7. 

9. The best accounts of patent medicines and medical quackery in American 
history are Young, Toadstool Millionaires (see chap. 3, n. 51); and idem. The 
Medical Messiahs: A Social History of Health Quackery in the Twentieth 
Century (Princeton, N.J.: Princeton University Press, 1967). His analysis of 
the appeal of patent medicines and of quackery provided a framework for 
examining unorthodox spotted fever therapies. 

10. "Makes a New Vaccine: Dr. Fox Finds Medicine Which Abrupts Tick 
Fever in Five Days," clipping dated 1916 in RML Scrapbook "1919— 1931." 

11. Flam to Parker, 18 December 1937, file "Cures for Spotted Fever (Letters 
offering to sell information)," RML Research Records. 

12. See correspondence and handbills dated April and May 1932 in file 
"Cures for Spotted Fever (Letters offering to sell information)," RML Research 
Records. 

13. J. J. Scott to Reserch Labritory [sic], [postmark 18 September 1938] 
file "Freak Letters," RML Research Records. 

14. Lizzie W. Sonyer [spelling unclear] to State Board of Health, Cheyenne, 
Wyoming, 28 August 1926, file "Freak Letters," RML Research Records. 

15. Cited in speech given by R. R. Parker "about 1940," and prepared for 
him by Hilda Holly from letters in file "Freak Letters," RML Research Records. 

16. Turnquist to Ludwik Anigstein, 5 June 1944, file "Cures for Spotted 
Fever (Letters offering to sell information)," RML Research Records; L. W. 
Hartman to W. M. Cobleigh, 25 July 19 21; and Cooley to Hartman, 15 
November 1921, box 10, folder E2, "Tick Control— General Correspondence, 
1918-1928," ZEA. 

17. Mrs. Charles H. Purkis to A. E. Lien, 7 May 1946, file "Cures for 
Spotted Fever (Letters offering to sell information)," RML Research Records. 

18. Cited in speech given by R. R. Parker "about 1940," and prepared 
for him by Hilda Holly from letters in file "Freak Letters," RML Research 
Records. 



320 



Notes to Pages 202-6 



19. Parker to A. E. Lien, 14 May 1946, file "Cures for Spotted Fever (Letters 
offering to sell information)," RML Research Records. 

20. Cited in speech given by R. R. Parker "about 1940," and prepared for 
him by Hilda Holly from letters in file "Freak Letters," RML Research Records. 

21. Cooper to Parker, 14 July 1936, file "Freak Letters," RML Research 
Records. 

22. Cooper to Parker, 25 July 1936, file "Freak Letters," RML Research 
Records. 

23. Sproat to Parker, 26 February 1941, file "Cures for Spotted Fever (Letters 
offering to sell information)," RML Research Records. 

24. My brief account of the sulfa drugs follow^s Harry F. Doweling, Fighting 
Infection: Conquests of the Twentieth Century (Cambridge, Mass.: Harvard 
University Press, 1977), 105-24. 

25. "Hope of Curing Tuberculosis, Influenza, and Leprosy," Science 80 
(i939):8. For popular response to the sulfa drugs, see also J. Stafford, "Pron- 
tosil Steals the Show at Major Medical Convention," Science 85 (1937) 19- 
10; "Gonorrhea Cured in 3 Days by Sulfanilamide," Science Newsletter 32 
(1937): 388; E. W. Murtfeldt, "King of Drugs," Popular Science 134 (i939):63 
ff.; "Killer Killed; Sulfapyridine Acts on All 32 Types of Pneumonia," Time 
33 (i939):28. 

26. Norman H. Topping, "Experimental Rocky Mountain Spotted Fever 
and Endemic Typhus Treated w^ith Prontosil or Sulfapyridine," Tub. Health 
Rep. 54 (1939): 1 143— 47; Edw^ard A. Steinhaus and R. R. Parker, "Experi- 
mental Rocky Mountain Spotted Fever: Results of Treatment with Certain 
Drugs," Tub. Health Rep. 58 (i943):35i-52; RML, Monthly Report, January 
1942, 3. 

27. Norman H. Topping, "Rocky Mountain Spotted Fever: Further Expe- 
rience in the Therapeutic Use of Immune Rabbit Serum," Pub. Health Rep. 
58 (i943):757-74 (quotation from p. 763). As recently as 1977, moreover, 
a professor of pediatrics at Mount Sinai School of Medicine in New York, 
felt it necessary to write a letter to the editor of the Journal of Pediatrics in 
which he reminded his colleagues of the danger of sulfonamides in rickettsial 
diseases. See Alex J. Steigman, "Rocky Mountain Spotted Fever and the Avoid- 
ance of Sulfonamides," Journal of Pediatrics 91 (1977): 163-64. 

28. "Green Light," Seattle [Wash.] Star^ 10 April 1937, clipping in RML 
Scrapbook "1932— 1940"; Clive Hirschorn, The Warner Bros. Story (New 
York: Crown Publishers, 1979), 172. 

29. Nick Kramis, interview by Victoria A. Harden, Hamilton, Montana, 7 
August 1985, NIAID files, NIH Historical Office (hereafter cited as Kramis 
interview); Ormsbee interview (see chap. 8, n. 69). 

30. See numerous clippings in all RML Scrapbooks. 

31. Kramis interview; many news clippings about civic clubs viewing this 
film, RML Scrapbooks; letters of permission to show film in file "R. R. Parker," 
box 91, "O-P," file 1650, "General Records of the National Institute of Health, 
1930-1948," NIH Records, Record Group 443, National Archives and Re- 
cords Administration, Washington, D.C. (hereafter cited as NIH Records). 
Copies of this film and of a later Kramis film entitled "The Story of Rocky 
Mountain Spotted Fever" are at NLM. 

32. R. R. Parker, "Tick-Borne Diseases of Man in Montana and Methods 
of Prevention" (see chap. 8, n. 67) (quotation from p. 12). 



Notes to Pages 206—8 



321 



33. RML, Annual Report, 1935, 3. 

34. Samuel F. Harby, "Tick Talk," Hygeia 22 (1944): 440— 41. 

35. George E. Baker, "Rocky Mountain Spotted Fever with Reference to 
Recognition, Prevention, and Treatment," Rocky Mountain Medical Journal 
35 (1938)136-43 (quotations from pp. 40—41). 

36. Norman H. Topping, "Rocky Mountain Spotted Fever: Treatment of 
Infected Laboratory- Animals with Immune Rabbit Serum," Pub. Health Rep. 
55 (1940): 4 1-4 6. At about the same time, Timothy J. Kurotchkin, J. van der 
Scheer, and Ralph W. G. Wyckoff at Lederle Laboratories also reported the 
results of their work using Cox's infected yolk sac material to develop an 
antiserum. Adapting the chemical procedures used in purif>'ing antipneumo- 
coccal rabbit serum, they stated that the toxic and allergic reactions of egg 
proteins could be avoided. This applied research at the NIH and at Lederle 
Laboratories was supplemented by more basic studies on how the immune 
serum protected. Ludwik Anigstein and his colleagues at the Universit)' of 
Texas Medical Branch in Galveston studied the production of local immunity 
at the site of subcutaneous or intradermal inoculation of immune serum as a 
step toward their goal of producing general immunit)-. See Timothy J. Ku- 
rotchkin, J. van der Scheer, and Ralph W. G. Wyckoff, "Refined Hyperimmune 
Rickettsial Sera," Proc. Soc. Exp. Biol. Med. 45 (i95o):323; Ludwik Anigstein, 
Madero N. Bader, and Gerald Young, "Protective Effect of Separate Inocu- 
lation of Spotted Fever Virus and Immune Serum by Intradermal Route," 
Science 98 (1943)1285-86; Ludwik Anigstein, Madero N. Bader, Gerald 
Young, and Dorothea Neubauer, "Protection against Spotted Fever by Specific 
Immune Serum Inoculated Intradermally at the Site of Infection," /. Immunol. 
48 (1944)169-77; Ludwik xA.nigstein, Dorothy Whitney, and Joe Beninson, 
"Inhibition of Typhus and Spotted Fever by Intradermal Inoculation of An- 
tiorgan or Certain Normal Sera," Proc. Soc. Exp. Biol. Med. 67 (i948):73— 
74. 

37. Norman H. Topping, "Rocky Mountain Spotted Fever: Further Expe- 
rience in the Therapeutic Use of Immune Rabbit Serum," Pub. Health Rep. 
58 (1943)1757-74; news release, file "R. R. Parker," box 91, "O-P," file 1650, 
"General Records of the National Institute of Health, 1930— 1948," NIH 
Records. Efficacy- figures are from the latter document. 

38. Parker to Rolla E. Dyer, 10 June 194 1, Notebook "R.M.S.E— Labo- 
ratorv^ Infections— Book I," R. R. Parker Notebooks, RML Research Records. 

39. Parker to Lewis R. Thompson, 26 May 1941, Notebook "R.M.S.E — 
Laboratory Infections— Book I," R. R. Parker Notebooks, RML Research 
Records. 

40. J. Frederick Bell, interview by Victoria A. Harden, Hamilton, Montana, 
6 August 1985, NIAID files, NIH Historical Office (hereafter cited as J. F. 
Bell interview). 

41. Hospital records, telegrams, press clippings, and internal correspondence 
about this case are in Notebook "R.M.S.E — Laboratory Infections— Book I," 
R. R. Parker Notebooks, RML Research Records; J. F. Bell interview. 

42. For a review of the work on a t\-phus antiserum and a report of the 
work of the Typhus Commission's test of its efficacy, see Andrew Yeomans, 
J. C. Snyder, and A. G. Gilliam, "The Effects of Concentrated Hyperimmune 
Rabbit Serum in Louse Borne Typhus," /AMA 129 (i945):i9-24. 



322 



Notes to Pages 2op~io 



43. James J. Sapero and Fred A. Butler, "Highlights on Epidemic Diseases 
Occurring in MiHtary Forces: In the Early Phases of the War in the South 
Pacific," ibid. 127 (i945):502— 6 (quotations from p. 502). 

44. Morbidity and mortality figures are from Theodore E. Woodward, 
Introduction to the History of the Armed Forces Medical Unit in Kuala Lum- 
pur, Malaya, and the Armed Forces Research Institute of Medical Sciences 
(AFRIMS) in Bangkok, Thailand, privately printed, n.d., 2. See also James B. 
Moe and Carl E. Pedersen, "The Impact of Rickettsial Diseases on Military 
Operations," Military Med. 145 (1980) 1780-8 5; Joseph F. Sadusk, Jr., "Ty- 
phus Fever in the United States Army Following Immunization," JAMA 133 
(1947): 1 192-99; C. B. Philip, "Tsutsugamushi Disease (Scrub Typhus) in 
World War II,"/. Parasitology 34 (i948):i69-9i; C. B. Philip, "Scrub Typhus 
and Scrub Itch," in Medical Department, U.S. Army, Preventive Medicine in 
World War II, vol. 7, Communicable Diseases: Arthropodborne Diseases 
Other Than Malaria (see chap. 9, n. 35), 275-347; C. J. D. Zarafonetis and 
M. P. Baker, "Scrub Typhus," in Medical Department, U.S. Army, Internal 
Medicine in World War II, vol. 2 (Washington, D.C.: Government Printing 
Office, 1963), 1 1 1-42. I am indebted to Margaret Pittman for bringing Dr. 
Woodward's recent work to my attention and to Dr. Woodward for providing 
a copy for the NIAID files, NIH Historical Office. 

45. The deaths of Sugata and Nishibe are noted in Parker to Cohn, 7 October 
1 94 1, Notebook "R.M.S.F. — Laboratory Infections— Book I," R. R. Parker 
Notebooks, RML Research Records. 

46. See a discussion of this in chap. 6. 

47. Bayne-Jones oral history, 3:677 (see chap. 9, n. 37); F. G. Blake, K. F. 
Maxcy, J. F. Sadusk, Jr., G. M. Kohls, and E. J. Bell, "Studies on Tsutsugamushi 
Disease (Scrub Typhus, Mite-Borne Typhus) in New Guinea and Adjacent 
Islands: Epidemiology, Clinical Observations, and Etiology in the Dobadura 
Area," Am. J. Hyg. 41 (i945):243-73; G. M. Kohls, C. A. Armburst, E. N. 
Irons, and C. B. Philip, "Studies on Tsutsugamushi Disease (Scrub Typhus, 
Mite-Borne Typhus) in New Guinea and Adjacent Islands: Further Obser- 
vations on Epidemiology and Etiology," Am. J. Hyg. 41 (1945): 374-99; 
C. B. Philip and G. M. Kohls, "Studies on Tsutsugamushi Disease (Scrub 
Typhus, Mite-Borne Typhus) in New Guinea and Adjacent Islands: Tsutsu- 
gamushi Disease with High Endemicity on a Small South Sea Island," Am. J. 
Hyg. 42 (i945):i95-202; C. B. Philip, T. E. Woodward, and R. R. Sullivan, 
"Tsutsugamushi Disease (Scrub or Mite-Borne Typhus) in the Philippine Is- 
lands During American Reoccupation in 1944-45," /• Trop. Med. 26 
(1946): 229-42. When the disease was identified in Burma, Thomas T. Mackie 
and A. G. Gilliam studied it at a laboratory established on the Irrawaddy 
River. 

48. Posters in NLM collection; "Protection against Scrub Typhus Mite," 
JAMA 128 (1945): 5 19; A. H. Madden, A. W. Lindquist, and E. F. Kipling, 
"Test of Repellents against Chiggers," /. Econ. Entomol. 37 (i944):283-86; 
R. C. Bushland, "New Guinea Field Tests of Uniforms Impregnated with 
Miticides to Develop Laundry-Resistant Clothing Treatments for Preventing 
Scrub Typhus," Am. J. Hyg. 43 (1946): 23 0-47; R. N. McCulloch, "Studies 
in the Control of Scrub Typhus," Med. J. Australia 1 (i946):7i7-38. 

49. Norman H. Topping, "Tsutsugamushi Disease (Scrub Typhus): Effects 
of Immune Rabbit Serum in Experimentally Infected Mice," Pub. Health Rep. 



Notes to Pages zio-ii 



60 (i945):i2i5-2o; "Vaccine for Scrub Typhus," Army & Navy Journal, 27 
March 1948, clipping in RML Scrapbook "1942- ," The danger of research 
on tsutsugamushi was underscored by the five investigators who lost their lives 
to laboratory-acquired infections. They were Dora Lush of the Walter and 
Eliza Hall Institute, Melbourne, Victoria, Australia; Richard G. Henderson 
of the NIH Division of Infectious Diseases; Philip Leroy Jones, a laboratory 
technician at the RML; David J. Hein of Lederle Laboratories; and Jewel E. 
Roberts, a pathologist in the U.S. Army Medical Corps. Henderson's assistant, 
Leroy A. Shelbaker, also contracted the disease and barely escaped death. 
Among researchers in the war zone, A. G. Gilliam suffered the disease and 
lent his name to one of the standard laboratory strains of tsutsugamushi. See 
Philip, "Tsutsugamushi in World War II," 188; "Names of Heroes of Science 
Belong on Honor Roll: Philip Leroy Jones Cited," Daily Missoulian, 3 June 
1945, clipping in RML Scrapbook "1943-1948." The "Gilliam" strain of 
tsutsugamushi was established by Norman Topping from a guinea pig inoc- 
ulated with GiUiam's blood; Norman H. Topping, personal communication 
to the author, 2 September 1988. It is referred to in J. E. Smadel, E. B. Jackson, 
B. L. Bennett, and F. L. Rights, "A Toxic Substance Associated with the Gilliam 
Strain of R. orientalis,'' Proc. Soc. Exp. Biol. Med. 62 (i946):i38-40. 

50. Richard A. Ormsbee, "Q Fever Rickettsia," in Horsfall and Tamm, eds., 
Viral and Rickettsial Infections of Man, 4th ed. (see chap, i, n. 7), 1144-63, 
esp. 1144-45. ^Iso the following series of papers on Mediterranean Q 
fever: F. C. Robbins and C. Ragan, " 'Q' Fever in Mediterranean Area: Report 
of Its Occurrence in Allied Troops: Clinical Features of the Disease," Am. J. 
Hyg. 44 (i946):6-22; R C. Robbins, R. L. Gauld, and E B. Warner, " 'Q' 
Fever in Mediterranean Area: Report of Its Occurrence in Allied Troops: 
Epidemiology," Am. J. Hyg. 44 (1946): 23-50; F. C. Robbins, R. Rustigan, 
M. J. Snyder, and J. E. Smadel, " 'Q' Fever in Mediterranean Area: Report 
of Its Occurrence in Allied Troops: Etiological Agent," Am. J. Hyg. 44 
(1946): 5 1—63; F. C. Robbins and R. Rustigan, " 'Q' Fever in Mediterranean 
Area: Report of Its Occurrence in AUied Troops: Laboratory Outbreak," Am. 
J. Hyg. 44 (i946):64-7i. 

51. T. E. Woodward and E. F. Bland, "Clinical Observations in Typhus 
Fever with Special Reference to the Cardiovascular System," JAMA 126 
(i944):287-93 (quotations from p. 287). 

52. G. T. Harrell, W. Venning and W. A. Wolff, "The Treatment of Rocky 
Mountain Spotted Fever," ibid., 929-34. See also idem, "The Treatment of 
Rocky Mountain Spotted Fever, with Particular Reference to Intravenous 
Fluids. A New Approach to Basic Supportive Therapy," ibid., 929-34; G. T. 
Harrell, W A. Wolff, W. Venning, and J. B. Reinhard, "The Prevention and 
Control of Disturbances of Protein Metabolism in Rocky Mountain Spotted 
Fever," Southern Medical Journal 39 (1946): 5 5 1-57. 

53. On the development of penicillin see Dowling, Fighting Infection, 125- 
57; A. N. Richards, "Production of Penicillin in the United States (1941- 
1946)," Nature 201 (i964):44i-45; H. W. Florey, "Steps Leading to the 
Therapeutic Application of Microbial Antagonisms," British Medical Bulletin 
4 (i946):248-58; Andre Maurois, The Life of Sir Alexander Fleming, Dis- 
coverer of Penicillin, trans. Gerard Hopkins (New York: E. P. Dutton, 1959); 
Lennard Bickel, Rise Up to Life: A Biography of Howard Walter Florey, Who 
Gave Penicillin to the World (New York: Charles Scribner's Sons, 1972); 



32.4 



Notes to Pages iii—i^ 



W. H. Helfand, H. B. Woodruff, K. M. H. Coleman, and D. L. Cowen, 
"Wartime Industrial Development of Penicillin in the United States," in John 
Parascandola, ed. The History of Antibiotics: A Symposium (Madison: Uni- 
versity of Wisconsin Press, 1980), 31—56. 

54. F. K. Fitzpatrick, "Penicillin in Experimental Spotted Fever," Science 
102 (i945):96-97. 

55. Hans Zinsser and E. B. Schoenbach, "Studies on Physiological Con- 
ditions Prevailing in Tissue Cultures,"/. Exp. Med. 66 (i937):207-27. 

56. J. C. Snyder, John Maier, and C. R. Anderson, Report to the Division 
of Medical Sciences (Washington, D.C.: National Research Council, 26 De- 
cember 1942). Because of wartime censorship, rickettsial investigators at uni- 
versities were not apprised of these findings. Thus in 1944 independent pub- 
lications appeared on the rickettsiostatic action of PABA, both on infected 
yolk sacs and in typhus-infected mice, and of toluidine blue, a thiazine dye 
used in bacteriological stains, on typhus-infected mice. See O. L. Peterson, 
"Therapeutic Effects of Forbisen and of Toluidine Blue on Experimental Ty- 
phus," Proc. Soc. Exp. Biol. Med. 55 (1944): 155—57. Donald Greiff, Henry 
Pinkerton, and Vicente Moragues, "Effect of Enzyme Inhibitors and Activators 
on the Multiplication of Typhus Rickettsiae: I. Penicillin, Para-Aminobenzoic 
Acid, Sodium Fluoride, and Vitamins of the B Group," /. Exp. Med. 80 

(1944) :56i-74; "Chemotherapy of Murine Typhus," /AMA 125 (i944):633. 

57. Their report was later published. See H. L. Hamilton, Harry Plotz, and 
J. E. Smadel, "Effect of p-Aminobenzoic Acid on the Growth of Typhus 
Rickettsiae in the Yolk Sac of the Infected Chick Embryo," Proc. Soc. Exp. 
Biol. Med. 58 (i945):255-62. 

58. Andrew Yeomans, J. C. Snyder, E. S. Murray, C. J. D. Zarafonetis, and 
R. S. Ecke, "The Therapeutic Effect of Para-Aminobenzoic Acid in Louse 
Borne Typhus Fever," JAMA 126 (i944):349— 56; see also correction to this 
article, ibid., 581; "Progress in the Treatment of Typhus Fever and of Rocky 
Mountain Spotted Fever," ibid., 964; Ludwik Anigstein and M. N. Bader, 
"Para-Aminobenzoic Acid— Its Effectiveness in Spotted Fever in Guinea Pigs," 
Science loi (i945):59i-92; H. M. Rose, R. B. Duane, and E. E. Fischel, "The 
Treatment of Spotted Fever with Para-Aminobenzoic Acid," JAMA 129 

(1945) :ii6o-6i. 

59. "Drug Cures Tick Fever When Rabbit Serum Fails," JAMA 131 

(1946) :i364; L. B. Flinn, J. W. Howard, C. W. Todd, and E. G. Scott, "Para- 
Aminobenzoic Acid Treatment of Rocky Mountain Spotted Fever," ibid. 132 
(i946):9ii-i4 (quotation from p. 914). 

60. S. F. Ravenel, "Para-Aminobenzoic Acid Therapy of Rocky Mountain 
Spotted Fever: Outline of a Comprehensive Plan of Treatment with Report 
of Five Cases," ibid. 133 (i947):989-94. Broad spectrum antibiotics, described 
later in this chapter, are also rickettsiostatic, suppressing the growth of rick- 
ettsiae until the body's own immune defenses can be marshalled. 

61. Dowling, Fighting Infection, 179. My discussion of the development of 
the broad-spectrum antibiotics follows ibid., 174-84. For other general surveys 
of this work, see idem, "History of the Broad Spectrum Antibiotics," Anti- 
biotics Annual, 195 8-1959 (New York: Medical Encyclopedia, 1959), 39- 
44; and idem. Medicines for Man: The Development, Regulation, and Use of 
Prescription Drugs (New York: Alfred A. Knopf, 1970). 

62. J. Ehrlich, Q. R. Bartz, R. M. Smith, D. A. Joslyn, and R R. Burkholder, 
"Chloromycetin, a New Antibiotic from a Soil Actinomycete," Science 106 



Notes to Pages 114—16 



32.5 



(i947):4i7. A few months later a second group of researchers at the University 
of Illinois obtained the same antibiotic from a fungus grown on the farm of 
the Illinois Agricultural Experiment Station in Urbana, Illinois. See H. E. 
Carter, D. Gottlieb, and H. W. Anderson, "Chloromycetin and Streptothricin," 
Science 107 (i948):ii3; Dowling, Fighting Infection, 308, n. 15. 

63. EhrUch, Bartz, Smith, Joslyn, and Burkholder, "Chloromycetin," 417. 

64. Woodward, History of the Armed Forces Medical Unit in Kuala Lumpur 
and the AFRIMS in Bangkok, 2. 

65. J. E. Smadel and E. B, Jackson, "Chloromycetin, an Antibiotic with 
Chemotherapeutic Activity in Experimental Rickettsial and Viral Infections," 
Science 106 (i947):4i8-i9. 

66. Dowling, Fighting Infection, 179-80; W. H. Mohrhoff and W. D. Moger- 
man, "Chloromycetin: Another Weapon for the Doctor's Arsenal," Process 
Industries Quarterly 12, no. i (i949):2-i4; H. L. Ley, Jr., and J. E. Smadel, 
"Antibiotic Therapy of Rickettsial Diseases," Antibiotics and Chemotherapy 
4 (i954):792-8o2; "Scrub Typhus Research Unit Returns to Malaya," JAMA 
139 (i949):io88. Duringthese tests, Smadel and Cornelius B. Philip contracted 
scrub typhus. In Philip's case, according to his son, Robert N. Philip, he was 
intentionally exposed to infected mites in a field test of the prophylactic efficacy 
of chloramphenicol. Both men returned to the United States shortly thereafter. 
Because they had not developed active immunity, each suffered a bout with 
the disease. Both recovered. See David B. Lackman, "Immunotherapy, Im- 
munoprophylaxis. Chemotherapy and Antibiotic Therapy: The Way It Was," 
manuscript, copy in NIAID files, NIH Historical Office; Robert N. Philip, 
personal communication to the author, 16 February 1988. 

67. M. C. Pincoffs, E. G. Guy, L. M. Lister, T. E. Woodward, and J. E. 
Smadel, "The Treatment of Rocky Mountain Spotted Fever with Chloro- 
mycetin," Ann. Int. Med. 29 (i948):656-63; M. J. Carson, L. F. Gowen, and 
F. R. Cochrane, "Rocky Mountain Spotted Fever Treated with Chloromycetin: 
Report of Two Cases,"/. Pediatrics 35 (i949):232— 34; J. D. Ratcliff, "Greatest 
Drug Since Penicillin," Collier's 123 (5 February i949):26ff. See also "Chlo- 
romycetin Claimed to be Effective in Rocky Mountain Spotted Fever Treat- 
ment," Am. J. Pub. Health 38 (1948): 1733; "Introducing Chloromycetin," 
Newsweek 30 (17 November 1947): 54; "First Artificially Made Miracle Drug: 
Chloramphenicol," Science Digest 26 (July 1949): 51. 

68. S. Ross, E. B. Schoenbach, F. G. Burke, M. S. Bryer, E. C. Rice, and 
J. A. Washington, "Aureomycin Therapy of Rocky Mountain Spotted Fever," 
JAMA 138 (I948):i2i3-i6. 

69. On the development of the tetracyclines, see Dowling, Fighting Infection, 
180-83. 

70. See, for example, Alan Gregg, "The Essential Need of Fundamental 
Research for Social Programs," Science loi (1945): 25 7— 59. 

71. Charles V. Kidd, "American Universities and Federal Research Funds," 
manuscript. National Institutes of Health, 1957, 288, copy in NIH Historical 
Office. 

72. Lawrence K. Frank, "Research after the War," Science loi (i945):433- 
34- 

73. For a discussion of these developments, see J. Merton England, A Patron 
for Pure Science: The National Science Foundation's Formative Years, 194 J- 
57 (Washington, D.C.: Government Printing Office, 1982); G. Burroughs 
Mider, "The Federal Impact on Biomedical Research," in John Z. Bowers and 



326 



Notes to Pages iiy-zo 



Elizabeth F. Purcell, eds., Advances in American Medicine: Essays at the Bi- 
centennial, 2. vols. (New York: Josiah Macy, Jr., Foundation, 1976) 2:806- 
71; Daniel M. Fox, "The Politics of the NIH Extramural Program, 1937- 
1950,"/. Hist. Med. Allied Sci. 42 {i^^j)\^^j-66. 

74. U.S. President's Scientific Research Board, Science and Public Policy : A 
Report to the President, by John R. Steelman, 5 vols. (Washington, D.C.: 
Government Printing Office, 1947); see esp. vol. 5, The Nation's Medical 
Research, 8, for definitions of basic and appHed research. 

75. For a chronology of these events, see U.S. National Institutes of Health, 
NIH Almanac, 1986 (Washington, D.C.: U.S. Department of Health and 
Human Services, NIH Publication no. 86-5, 1986), esp. 3-18; MAID, In- 
tramural Contributions, iSSj-i^Sy (see chap. 9, n. 11), 3-7. 

76. "Spotted Fever Vaccine Distribution Discontinued," JAMA 140 
(i949):337; "Malone, Tick Vaccine Maker, Honored at Retirement Party," 
Ravalli Republican, 3 July 1958; and "Earl Malone Retires from Work at Lab 
after 34 Years on Job," Western News, 3 July 1958, clippings in RML Scrap- 
book "1942- ." 

77. My discussion of this is taken from a transcript of a conference held at 
the RML, 13-14 January 1949, in Notebook "Haas Conference — 1949," 
R. R. Parker Notebooks, RML Research Records. 

78. Ibid., II. 

79. "Rocky Mountain Laboratory Head Dies at 61," Daily Missoulian, 5 
September 1949; "Dr. R. R. Parker, 61, Laboratory Director and Noted Sci- 
entist, Dies Unexpectedly; Funeral Services Set for 2 p.m. Friday," n.d.; and 
"Noted Tick Fever Expert Succumbs," 4 September 1949, clippings in RML 
Scrapbook "1949- ." 

80. Russell M. Wilder, "The Rickettsial Diseases: Discovery and Conquest," 
Arch. Pathol. 49 (i95o):479-89 (quotation from p. 489). 

Chapter Eleven: Spotted Fever after Antibiotics 

1. J. E. McCroan, R. L. Ramsey, W. J. Murphy, and L. S. Dick, "The Status 
of Rocky Mountain Spotted Fever in the Southeastern United States," Pub 
Health Rep. 70 (195 5): 3 19— 25; J. E. Smadel, "Status of the Rickettsioses in 
the United States," Ann. Int. Med. 51 (i959):42i-35. 

2. Although related tick-borne rickettsioses exist in other parts of the w^orld, 
Rickettsia rickettsii has never been isolated outside the w^estern hemisphere. 

3. The occurrence of Rocky Mountain spotted fever in Sao Paulo and Minas 
Gerais, Brazil, was discussed in chap. 8. Spotted fever was first reported from 
the state of Rio de Janeiro, Brazil, in 1941. See J. Tostes and G. Bretz, "Sobre 
uma rickettsioses observada em zona rural do Estado do Rio de Janeiro," 
Brasil Med. 55 (i94i):789-94. 

4. R. J. Gibbons, "Survey of Rocky Mountain Spotted Fever and Sylvatic 
Plague in Western Canada During 1938," Canadian Journal of Public Health 
30 (i939):i84-87; M. R. Bow and J. H. Brown, "Rocky Mountain Spotted 
Fever in Alberta, 1935-1950," ibid. 43 (i952):i09-i5. 

5. F. A. Humphreys and A. G. Campbell, "Plague, Rocky Mountain Spotted 
Fever, and Tularaemia Surveys in Canada," ibid. 38 (i947):i24— 30. A 1964 
serological study in the Ottawa, Ontario, area demonstrated spotted fever 
antibodies in wild animals and in humans, even though no cases had been 



Notes to Page 221 



327 



reported from eastern Canada. See V. F. Newhouse, J. A. McKiel, and W. 
Burgdorfer, "California Encephalitis, Colorado Tick Fever and Rocky Moun- 
tain Spotted Fever in Eastern Canada: Serological Evidence," ibid. 55 
(i964):257-6i. 

6. G. E. Davis, "Experimental Transmission of the Rickettsiae of the Spotted 
Fevers of Brazil, Colombia, and the United States by the Argasid Tick Or- 
nithodoros nicollei,'" Pub. Health Rep. 58 (1943): 1742-44. 

7. M. E. Bustamante and G. Varela, "Una nueve rickettsiosis en Mexico. 
Existencia de la fiebre manchada americana en los Estados de Sinaloa y So- 
nora," Revista del Instituto de Saluhridad y Enfermedades Tropicales 4 
(1943): 189-210 (hereafter cited as Rev. Inst, de Sal. y Enf. Tropicales); idem, 
"Caracteristicas de la fiebre manchada de las Montanas rocosas en Sonora y 
Sinaloa, Mexico," ibid. 5 (1944): 129-36; idem, "Aislamiento de Una Cepa 
de Fiebre Manchada Identica a la de las Montanas Rocosas en Sinaloa, 
Mexico," Bol. Offtc. San. Panam. 23 (i944):ii7-i8. 

8. M. E. Bustamante and G. Varela, "Distribucion de las Rickettsiasis en 
Mexico," Rev. Inst. deSal. yEnf. Tropicales 8 (1947) 13-1 4; M. E. Bustamante, 
G. Varela, and C. Orbiz-Marcotte, "II. Estudios de fiebre manchada en la 
Laguna," ibid. 7 ( 1946): 39-48 ; M. E. Bustamante and G. Varela, "III. Estudios 
de fiebre manchada en Mexico. Hallazgo del Amblyomma cajennese natur- 
almente infectado en Vera Cruz," ibid. 7 (i946):75— 78; R. Silva-Goytia and 
A. Elizondo, "Estudios sobre Fiebre Manchada en Mexico. I. Clasificacion de 
Cepas," Medicina Revista Mexicana 32 (i952):2i7— 21; R. Silva-Goytia and 
A. Elizondo, "Estudios sobre Fiebre Manchada en Mexico. II. Parasitos he- 
matofagos encontrados naturalmente infectados," Med. Rev. Mexicana 32 
(i952):278-82; R. Silva-Goytia, H. Vasquez Campos, and A. Elizondo, "Es- 
tudios sobre Fiebre Manchada en Mexico. V. Incidencia de anticuerpos es- 
pecificos para Dermacentroxenus rickettsi en grupos ocupacionales de diversas 
areas geograficas," Med. Rev. Mexicana 33 (i953):425-35. 

9. E. C. de Rodaniche and A. Rodaniche, "Spotted Fever in Panama: Isolation 
of the Etiologic Agent from a Fatal Case," Am. J. Trop. Med. 30 (1950): 511- 
17; C. Calero, J. M. Nunez, and R. Silva-Goytia, "Rocky Mountain Spotted 
Fever in Panama: Report of Two Cases," American Journal of Tropical Med- 
icine and Hygiene i {i9$z):6^i—}6; E. C. de Rodaniche, "Natural Infection 
of the Tick, Amblyomma cajennese, v^ith Rickettsia rickettsii in Panama," 
Am. J. Trop. Med. Hyg. 2 (i953):696-99 (quotation from p. 698). In 1976, 
Rocky Mountain spotted fever was also reported from Costa Rica. See L. G. 
Fuentes, "Primer caso de fiebre de las Montanas Rocosas en Costa Rica, 
America Central," Revista Latinoamericana de Microbiologia 21 (1979): 167- 
72; J. Tosi, "Mapa ecologico (Republica de Costa Rica): Segun la clasificacion 
de zonas de Vida del mundo de L. R. Holdridge." Centro Cientifico Tropical, 
de San Jose, Costa Rica (Mapa); L. Fuentes, "Ecological Study of Rocky 
Mountain Spotted Fever in Costa Rica," Am. J. Trop. Med. Hyg. 35 
(i986):i92-96. 

10. Bustamante and Varela, "Distribucion de las Rickettsiasis en Mexico," 
14; A. Vallejo-Freire, "Spotted Fever in Mexico: Immunological Relationship 
between the Virus of the Rickettsiosis Observed in Sonora and Sinaloa, Mexico, 
and Other Spotted Fever Viruses," Mem. Inst. Butantan 19 (i946):i59-8o; 
W. M. Kelsey and G. T. Flarrell, "Management of Tick Typhus (Rocky Moun- 
tain Spotted Fever) in Children," /AMA 137 (i948):i356-6i. 



328 



Notes to Pages izz-zj 



11. In contrast, Rocky Mountain spotted fever was conspicuously not a 
topic of general press interest in this period. Between 1952 and 1963, the 
Reader's Guide to Periodical Literature carried no entries for articles about 
the disease. 

12. C. L. Williams, "The Control of Murine Typhus with DDT," Military 
Surgeon 104 (1949): 163-67; "Control of Murine Typhus with DDT," ]AMA 
140 (i949):878; McCroan, Ramsey, Murphy, and Dick, "Status of Rocky 
Mountain Spotted Fever in the Southeastern United States," 323-24; J. E. 
McCroan, Jr., and R. L. Ramsey, "DDT Dusting as a Control Measure for 
the American Dog Tick, the Vector of Rocky Mountain Spotted Fever in 
Georgia," Journal of the Medical Association of Georgia 36 (i947):242— 44; 
"Speech by Dr. Heitor R Froes," in Whitlock, ed.. Proceedings of the Fourth 
International Congress on Tropical Medicine and Malaria (see chap. 8, n. 27), 
19. 

13. Rachel Carson, Silent Spring (Boston: Houghton Mifflin Co., 1962), 
268—69. See also A. W. A. Brown, Insecticide Resistance in Arthropods^ World 
Health Organization Monograph Series no. 38 (Geneva: World Health Or- 
ganization, 1958); A. W. A. Brown, "The Challenge of Insecticide Resistance," 
Bulletin of the Entomological Society of America 7 (i96i):6— 19. 

14. McCroan, Ramsey, Murphy, and Dick, "Status of Rocky Mountain 
Spotted Fever in the Southeastern United States," 321; D. B. Lackman and 
R. K. Gerloff, "The Effect of Antibiotic Therapy upon Diagnostic, Serologic 
Tests for Rocky Mountain Spotted Fever," Public Health Laboratory 11 
(i953):97-99- 

15. Mary Barber and Lawrence P. Garrod, Antibiotic and Chemotherapy 
(Edinburgh: E. & S. Livingstone, 1963), 116—28 (quotation from p. 123); 
"Dangerous Drugs?" Newsweek 41 (12 January i953):74; "Drugs Are Dan- 
gerous, Too," Time 60 (25 August 195 2): 59; "Chloromycetin Dangers In- 
vestigated After Death," Science Newsletter 62 (19 July i952):43; "Chloro- 
mycetin Problem," Scientific American 189 (September i9^z):jzif.; "Danger 
in Miracles," Newsweek 53 (18 May i959):io6. 

16. R. Milch, D. Rail, and J. Tobie, "Bone Localization of the Tetracyclines," 
/. Nat. Cancer Inst. 191 (i957):87-9i. 

17. I. S. Wallman and H. B. Hilton, "Teeth Pigmented by Tetracycline," 
Lancet i (1962): 8 27-29; idem, "Prematurity, Tetracychne, and Oxytetracy- 
cline in Tooth Development," ibid. 2 (i962):720— 21; C. J. Witkop, Jr., and 
R. O. Wolf, "Hypoplasia and Intrinsic Staining of Enamel Following Tetra- 
cycline Therapy," JAMA 185 (i963):ioo8-ii (quotation from p. 1008). 
Thanks are due to the staff of the public information office of the National 
Institute of Dental Research for alerting me to these early papers. 

18. "Prescribing of Tetracycline to Children," JAMA 238 (1977): 5 79. 

19. Kidd, "American Universities and Federal Research Funds" (see chap. 
10, n. 71), 283. See also his table 41, p. 284, for amounts expended. 

20. Dowling, Fighting Infection (see chap. 10, n. 24), 248; Dorland J. Davis, 
interview by Victoria A. Harden, Bethesda, Maryland, 27 February 1985, 
NIAID files, NIH Historical Office. 

21. The apocryphal story has no single origin— I have heard it told by a 
variety of people on different occasions. Another version is noted in Sheldon 
G. Cohen and William R. Duncan, "Immunology and NIAID (i 887-1970)," 
in NIAID, Intramural Contributions, 1887-1987 (see chap. 9, n. 11), 96. 



Notes to Pages iz^-zj 



329 



22. U.S. President's NIH Study Committee, Biomedical Science and Its 
Administration: A Study of the National Institutes of Health (Washington, 
D.C.: Government Printing Office, 1965), 153-57. 

23. P. B. Beeson, "Infectious Diseases (Microbiology)," in Bowers and Pur- 
cell, eds.. Advances in American Medicine (see chap. 10, n. 73), 1:136-40 
(quotation from p. 136). My discussion of the Commission on Rickettsial 
Diseases was guided by conversations with Charles L. Wisseman, Jr., on 5 
November 1987 and on 24 March 1988. Dr. Wisseman is preparing a much 
needed history of the commission, which he headed between i960 and 1973. 
The figures for awards are taken from the conversation with Dr. Wisseman 
and from Joseph E. Smadel, "Remarks of Director, Commission on Rickettsial 
Diseases, at Semiannual Meeting of Armed Forces Epidemiological Board," 9 
December 1957, copy in NIAID files, NIH Historical Office. 

24. My totals, from NIH Almanac, 1983, 130. 

25. My discussion of these centers was initially guided by Richard A. Orms- 
bee in a personal communication, 10 March 1986. 

26. My discussion of rickettsial grants is taken from yearly NIH grants 
publications and data bases, 1947— present. See Note on Sources for specific 
titles. John P. Fox was funded for research on typhus from 1952 through 1961 
at Tulane University and later at the Public Health Research Institute of New 
York City; H. J. Wisniewski of the Milwaukee Health Department received 
small grants to survey the epidemiology of rickettsial diseases in the Milwaukee, 
Wisconsin, area; Harry B. Harding and Opal E. Hepler of Northwestern 
University School of Medicine in Chicago were funded between 1953 and 
i960 for immunologic studies including serologic tests for rickettsial diseases; 
microbiologists Freeman A. Weiss and Trygve O. Berge received support for 
the preservation and expansion of the rickettsial registry at the American Type 
Culture Collection, now at Rockville, Maryland; Richard B. Loomis of the 
California State College at Long Beach was funded for research on chigger 
mites, the vectors of scrub typhus; Robert Traub of the University of Maryland 
School of Medicine was supported for research on fleas, the vectors of murine 
typhus; Traub and colleague Charles L. Wisseman, Jr., studied the ecology 
and vectors of rickettsial infections in West Pakistan through the University 
of Maryland's International Center. For Rocky Mountain spotted fever as an 
individual topic of study, the picture was bleak during the 1950s. One lone 
grant of $3,742 was awarded to D. E. Beck at Brigham Young University in 
Provo, Utah, for research on parasitic arthropods related to spotted fever. 

27. V. K. Zworykin, J. Hillier, and A. W. Vance, "An Electron Microscope 
for Practical Laboratory Service," Transactions of the American Institute of 
Electrical Engineers 60 (1941)1157—61; V. K. Zworykin and J. HilHer, "A 
Compact High Resolving Power Electron Microscope," Journal of Applied 
Physics 14 (1943)1658-83. 

28. S. Mudd and T. F. Anderson, "Pathogenic Bacteria, Rickettsias, and 
Viruses as Shown by the Electron Microscope: Their Relationships to Immunity 
and Chemotherapy. 1. Morphology," JAMA 126 (i944):56i— 70 (quotation 
from p. 561); S. Mudd, "Pathogenic Bacteria, Rickettsias, and Viruses as 
Shown by the Electron Microscope: Their Relationships to Immunity and 
Chemotherapy. II. Relationships to Immunity," ibid. 632-39 (quotation from 
pp. 632-33). 

29. H. Plotz, J. E. Smadel, T. F. Anderson, and L. A. Chambers, "Mor- 
phological Structure of Rickettsiae," /. Exp. Med. jj (1943)^3 5 5-5 8. 



330 



Notes to Pages 218-19 



30. Ibid., 357. Spencer and Parker's finding of invisible forms of rickettsiae 
was discussed in chap. 7. Copy of their paper with marginal note in NIAID 
files, NIH Historical Office. Lucille Jamieson Weiss of the Lilly Research 
Laboratories in Indianapolis also pubHshed electron micrographs of typhus 
rickettsiae, which showed the small forms dividing, an indication that they 
were indeed living organisms. See L. J. Weiss, "Electron Micrographs of Rick- 
ettsiae of Typhus Fever,"/. Immunol. 47 (i943):353-57. In a personal com- 
munication to the author, 30 November 1988, David H. Walker cautioned 
that the electron micrographs did not constitute proof that these small forms 
were rickettsiae and noted that they would have to be purified free of classic 
forms and then demonstrated to be infective. 

31. Mudd, "Pathogenic Bacteria, Rickettsias, and Viruses. II. Relationships 
to Immunity," 633. 

3 2. M. Ruiz Castaneda and Roberto Silva-Goytia of the Public Health Service 
and the Department of Medical Research, General Hospital, Mexico City, for 
example, found antigenic similarities between typhus and spotted fever to be 
considerably greater than expected. Their studies indicated that deficiency in 
one important immune factor might explain the failure of total cross-protection 
in guinea pigs. See M. Ruiz Castaneda and R. Silva-Goytia, "Immunological 
Relationship between Spotted Fever and Exanthematic Typhus," /, Immunol. 
42 (1941):!— 14. For confirmation of this work in the United States, see 
H. Plotz, B. Bennett, K. Wertman, and M. Snyder, "Cross-Reacting Typhus 
Antibodies in Rocky Mountain Spotted Fever," Proc. Soc. Exp. Biol. Med. 57 
(i944):336-39. 

33. A. Pijper and C. G. Crocker, "Rickettsioses of South Africa," South 
African Medical Journal 12 (193 8): 61 3-30 (quotation from p. 614). 

34. H. Plotz, R. L. Reagan, and K. Wertman, "Differentiation between 
Fievre Boutonneuse and Rocky Mountain Spotted Fever by Means of Com- 
plement Fixation," Proc. Soc. Exp. Biol. Med. 55 (i944):i73-76; D. B. Lack- 
man and E. G. Pickens, "Antigenic Types in the Rocky Mountain Spotted 
Fever Group of Rickettsiae," Bacteriological Proceedings 3 (i953):2i9;F. M. 
Bozeman, J. W. Humphries, J. M. Campbell, and P. L. O'Hara, "Laboratory 
Studies of the Spotted Fever Group of Rickettsiae," in Symposium on the 
Spotted Fever Group, Walter Reed Army Institute of Research Medical Science 
Publication no. 7 (Washington, D.C.: Government Printing Office, i960), 7- 
11; E. J. Bell and H. G. Stoenner, "Immunologic Relationships Among the 
Spotted Fever Group of Rickettsias Determined by Toxin Neutralization Tests 
in Mice with Convalescent Animal Serums,"/. Immunol. 84 (i96i):737-46; 
H. G. Stoenner, D. B. Lackman, and E. J. Bell, "Factors Affecting the Growth 
of Rickettsias of the Spotted Fever Group in Fertile Hens' Eggs," /. Inf. Dis. 
no (i962):i2i-28; E. G. Pickens, E. J. Bell, D. B. Lackman, and W. Burg- 
dorfer, "Use of Mouse Serum in Identification and Serologic Classification of 
Rickettsia akari and Rickettsia australis,'' J. Immunol. 94 (i965):883-89. 

35. R. R. Parker, G. M. Kohls, G. W. Cox, and G. E. Davis, "Observations 
on an Infectious Agent from Amblyomma maculatum,'' Pub. Health Rep. 54 
(1939): 1482-84; D. B. Lackman, R. R. Parker, and R. K. Gerloff, "Serological 
Characteristics of a Pathogenic Rickettsia Occurring in Amblyomma macu- 
latum,'' ibid. 64 (i949):i342-49. 

36. D. B. Lackman, E. J. Bell, H. G. Stoenner, and E. G. Pickens, "The 
Rocky Mountain Spotted Fever Group of Rickettsias," Health Laboratory 



Notes to Pages zz^—jo 



331 



Science 2 (i965):i35-4i. Surprisingly, toxin neutralization tests revealed that 
R. parkeri was closely related to Rickettsia conorii, which caused boutonneuse 
fever. 

37. Rickettsia montana was originally designated Eastern Montana agent. 
See E. J. Bell, G. M. Kohls, H. G. Stoenner, and D. B. Lackman, "Non- 
pathogenic Rickettsias Related to the Spotted Fever Group Isolated from Ticks, 
Dermacentor variabilis and Dermacentor andersoni from Eastern Montana," 
/. Immunol. 90 (i963):770— 81; Lackman, Bell, Stoenner, and Pickens, "Rocky 
Mountain Spotted Fever Group of Rickettsias," 137. The Western Montana 
U strain of R. rickettsii was found to be similar to but not identical with 
R. montana in the production of antibodies. See W. H. Price, "The Epide- 
miology of Rocky Mountain Spotted Fever. I. The Characterization of Strain 
Virulence of Rickettsia rickettsii,'' Am. J. Hyg. 58 (i953):248-68. 

38. Lackman, Bell, Stoenner, and Pickens, "Rocky Mountain Spotted Fever 
Group of Rickettsias," 138; P. F. Zdrodovskii and H. M. Golinevich, The 
Rickettsial Diseases, trans. B. Haigh (New York: Pergamon, i960). Mild 
clinical symptoms of North Asian tick typhus and an eschar at the site of the 
tick bite initially indicated that Rickettsia sibirica might be related to bou- 
tonneuse fever. A strong cross-reaction with Rickettsia rickettsii in the toxin- 
neutralization test, however, demonstrated that instead its antigens were more 
hke those of the Rocky Mountain spotted fever organism. Cornelius B. Philip 
suggested that the ecology of the North Asian organism was more comparable 
to the ecology of R. rickettsii than to that of R. conorii. See E. J. Bell and 
H. G. Stoenner, "Immunologic Relationships Among the Spotted Fever Group 
of Rickettsias Determined by Toxin Neutralization Tests in Mice with Con- 
valescent Animal Serums,"/. Immunol. 84 (i960): 171-82; C. B. Philip, "Some 
Epidemiological Considerations in Rocky Mountain Spotted Fever," Pub. 
Health Rep. 74 (1959): 595-600. For more recent research on this disease, see 
Fan Ming-yuan, David H. Walker, Yu Shu-rong, and Liu Qing-huai, "Epi- 
demiology and Ecology of Rickettsial Diseases in the People's Republic of 
China," Reviews of Infectious Diseases 9 (i987):823-4o; Jia Gang Wang and 
David H. Walker, "Identification of Spotted Fever Group Rickettsiae from 
Human and Tick Sources in the People's Republic of China," /. Inf. Dis. 156 
(19 87): 665-69; and Fan Ming-yuan, David H. Walker, Liu Qing-huai, Li Fian, 
Bai Hai-chun, Zhang Jia-Ke, Brenda Lenz, and Cai Hong, "Rickettsial and 
Serologic Evidence for Prevalent Spotted Fever Rickettsiosis in Inner Mon- 
goHa," Am. J. Trop. Med. Hyg. 36 (i987):6i5-20. 

39. In 195 1 investigators at the RML reported that neither R. australis nor 
R. akari provided any immunity to guinea pigs against challenge with Rocky 
Mountain spotted fever. All the other spotted fever group organisms provided 
some measure of protection, although not complete. See D. B. Lackman and 
R. R. Parker, "The Serological Characterization of North Queensland Tick 
Typhus," Pub. Health Rep. 63 (i948):i624-28; R. R. Parker, E. G. Pickens, 
D. B. Lackman, E. J. Bell, and F. B. Thrailkill, "Isolation and Characterization 
of Rocky Mountain Spotted Fever Rickettsiae from the Rabbit Tick Hae- 
maphysalis leporis-palustris Packard," ibid. 66 (195 1):45 5-63; Pickens, Bell, 
Lackman, and Burgdorfer, "Use of Mouse Serum in Identification and Serologic 
Classification of Rickettsia akari and Rickettsia australis,'' 883-89. For ad- 
ditional information on Queensland tick typhus, see H. R. Cox, "The Spotted 
Fever Group," in Thomas M. Rivers and Frank L. Horsfall, Jr., eds.. Viral 



332 



Notes to Page 130 



and Rickettsial Infections ofMan^ 3d ed. (Philadelphia: J. B, Lippincott, 1959), 
856-58. 

40. Lackman, Bell, Stoenner, and Pickens, "Rocky Mountain Spotted Fever 
Group of Rickettsias," 140. Their grouping was confirmed in 1978 by yet 
another RML group using a technique called microimmunofluorescence, which 
exploited the ability to "tag" particular antigens on the organisms with material 
that fluoresced. See R. N. Philip, E. A. Casper, W. Burgdorfer, R. K. Gerloff, 
L. E. Hughes, and E. J. Bell, "Serologic Typing of Rickettsiae of the Spotted 
Fever Group by Microimmunofluorescence,"/. Immunol. 121 (i978):i96i- 
68. During this study, moreover, Philip and his colleagues identified a new 
nonpathogenic, tick-borne rickettsial species, which they named R. bellii after 
E. John Bell. The new organism was distinct from both the spotted fever group 
and the typhus group rickettsiae. See R. N. Philip, E. A. Casper, R. L. Anacker, 
J. Cory, S. F. Hayes, W. Burgdorfer, and C. E. Yunker, ''Rickettsia bellii sp. 
Nov.: A Tick-Borne Rickettsia, Widely Distributed in the United States, That 
Is Distinct from the Spotted Fever and Typhus Biogroups," International Jour- 
nal of Systematic Bacteriology 33 (i983):94-io6. 

41. R. L. Anacker, T. F. McCaul, W. Burgdorfer, R. K. Gerloff, "Properties 
of Selected Rickettsiae of the Spotted Fever Group," Infection and Immunity 
27 (i98o):468-74; W. F. Myers and C. L. Wisseman, Jr., "The Taxonomic 
Relationship of Rickettsia canada to the Typhus and Spotted Fever Groups 
of the Genus Rickettsia,'' in Burgdorfer and Anacker, eds., Rickettsiae and 
Rickettsial Diseases (see chap. 9, n. 14), 313—25; C. L. Wisseman, "Some 
Biological Properties of Rickettsiae Pathogenic for Man," in Burgdorfer and 
Anacker, eds., Rickettsiae and Rickettsial Diseases, 298; Charles L. Wisseman, 
Jr., personal communication to the author about unpublished data, 24 March 
1988. An alternative grouping for the spotted fever group rickettsiae suggested 
by this work is: 

A— R. rickettsii, R. conorii and other organisms, not yet fully characterized, recovered 
from victims of spotted fever group rickettsial disease in Israel, India, and else- 
where 

B— R. sibirica and R. montana 
C — R. australis and R. akari 

42. N. H. Topping, R. Helig, and V. R. Naidu, "A Note on the Rickettsioses 
in India," Pub. Health Rep. 58 (i943):i2o8-io; D. R. Seaton and M. G. P. 
Stoker, "A Serological Analysis of Typhus Cases in India by Weil-Felix, Rick- 
ettsial Agglutination, and Complement-Fixation Tests," Annals of Tropical 
Medicine 40 (i946):347-57; S. L. Kalra, "Natural History of Typhus Fevers 
in India," Indian Journal of Medical Sciences 6 (195 2): 5 69-75; R. G. Rob- 
ertson, C. L. Wisseman, Jr., and R. Traub, "Tick-borne Rickettsia of the 
Spotted Fever Group in \5C^est Pakistan. I. Isolation of Strains from Ticks in 
Different Habitats," Am. J. Epidemiol. 92 (i97o):382-94; R. G. Robertson 
and C. L. Wisseman, "Tick-borne Rickettsiae of the Spotted Fever Group in 
West Pakistan. II. Serological Classification of Isolates from West Pakistan and 
Thailand: Evidence for Two New Species," Am. J. Epidemiol. 97 (1973 ): 55- 
64; S. Stephen, H. L. Rao, and K. N. Achyutha Rao, "Serological Evidence 
of Infection by Spotted Fever Group Rickettsiae in Karnataka State," Indian 
Journal of Medical Research 72 (i98o):3 52-54. 

43. F. Mahara, K. Koga, S. Sawada, T. Taniguchi, F. Shigemi, T. Suto, 
Y. Tsubio, A. Ooya, H. Koyama, T. Uchiyama, et al., "The First Report of 



Notes to Page z^o-^i 



333 



the Rickettsial Infections of Spotted Fever Group in Japan: Three Chnical 
Cases" (in Japanese), Kansenshogaku Zasshi 59 (1985):! 165-71. 1 am grateful 
to Dr. Yoichiro Ito for translating this paper for me. See also a report of 
spotted fever group infections in Kyushu in S. Yamamoto, N. Kawabata, T. 
Uchiyama, and T. Uchida, "Evidence for Infection Caused by Spotted Fever 
Group Rickettsia in Kyushu, Japan," Japanese Journal of Medical Science and 
Biology 40 (19 8 7): 7 5-78. 

44. D. Beytout, "Rickettsioses diagnostiquee par microagglutination de Jan- 
vier a Juin 1963 a Saigon," Bull. Soc. Path. Exotique 57 (i964):257-63; 
N. J. Marchette, "Rickettsioses (Tick Typhus, Q Fever, Urban Typhus) in 
Malaya," Journal of Medical Entomology 2 (i966):339-7i; R. Brezina, R 
Ac, J. Rehacek, and M. Majerska, "Tv^o Strains of Rickettsiae of Rocky 
Mountain Spotted Fever Group Recovered from Dermacentor marginatus 
Ticks in Czechoslovakia: Results of Preliminary Serological Identification," 
Acta Virologica 13 (1969): 142-45; J. Rehacek, R. Brezina, R Ac, M. Zu- 
pancicova, and E. Kovacova, "Contribution to the Natural Focalit>^ of Rick- 
ettsiae Belonging to the Rocky Mountain Spotted Fever (RMSF) Group in 
Slovakia," Folia Parasitologica 19 (i972):4i-52. On the present status of 
rickettsial nomenclature, see R. N. Philip, "Some Comments about the Sys- 
tematics of Rickettsiae," in "Festschrift for Cornelius Becker Philip" (special 
issue), Myia 3 (198 5): 209— 17. 

45. On spotted fever group rickettsioses in Africa since World War II, see 
A. D. Charters, "Tick Typhus in Abyssinia," Transactions of the Royal Society 
of Medicine and Hygiene 39 (i946):335-42; G. W. A. Dick and E. A. A. 
Levels, "A Rickettsial Disease in East Africa Transmitted by Ticks {Rhipice- 
phalus simus and Haemaphysalis leachi),'" ibid. 41 (1947): 29 5-3 26; G. M. 
Findlay and G. T. L. Archer, "The Occurrence of Tick-Borne Typhus in West 
Africa," ibid. 41 (i948):8i5-i8; P. Giroud, "Les Rickettsioses en Afrique 
equatoriale," Bulletin of the World Health Organization 4 (i95i):535— 46; P. 
Le Gac, P. Giroud, and C. Lemaigre, "La Foret equatoriale doit-elle etre 
consideree comme une zone endemique des rickettsioses? Comportment des 
pygmees de la Lobaye, Oubangui-Chari (A.E.F.) vis-a-vis des antigenes des 
typhus epidemique, murin, de la fievre boutonneuse, et de la fievre Q," Bull. 
Soc. Path. Exotique 45 (19 5 2): 599-602; R. B. Heisch, R. McPhee, and L. R. 
Rickman, "The Epidemiology of Tick-Typhus in Nairobi," East African Med- 
ical Journal 34 (i957):459-77; R. Kirk, "Rickettsial Infections in the Sudan 
Republic,"/. Trop. Med. Hyg. 62 (i959):279-84; J. Jadin, "Les Rickettsioses 
en Afrique centrale," Bull. Soc. Path. Exotique 56 (i963):57i-86; H. Hoogs- 
traal, "Ticks in Relation to Human Diseases Caused by Rickettsia Species," 
Annual Review of Entomology 12 (i967):377-42o; F. Weyer, "Progresses in 
Ecology and Epidemiology of Rickettsioses," Acta Tropica 35 (i978):5-2i. 

46. W. Burgdorfer, A. Aeschlimann, O. Peter, S. F. Hayes, and R. N. Philip, 
''Ixodes ricinus: Vector of a Hitherto Undescribed Spotted Fever Group Agent 
in Sw^itzerland," Acta Tropica 36 (i979):357-67; W Burgdorfer, S. F. Hayes, 
L. A. Thomas, and J. L. Lancaster, Jr., "A New Spotted Fever Group Rickettsia 
from the Lone Star Tick, Amblyomma americanum^' in Burgdorfer and An- 
acker, eds., Rickettsiae and Rickettsial Diseases, 595-602. The Swiss organism 
has been named Rickettsia helvetica. 

47. Gerard J. Tortora, Berdell R. Funke, and Christine L. Case, Microbi- 
ology: An Introduction, 2d ed. (Menlo Park, Calif.: Benjamin/Cummings 



334 



Notes to Pages i^i-^i 



Publishing Co., 1986), chaps. 9, 12; H. Ris and J. P. Fox, "The Cytology of 
Rickettsiae,"/. Exp. Med. 89 (i949):68i-86. 

48. M. R. Bovarnick and J. C. Snyder, "Respiration of Typhus Rickettsiae," 
]. Exp. Med. 89 (i949):56i-65; C. L. Wisseman, Jr., E. B. Jackson, F. E. 
Hahn, A. C. Ley, and J. E. Smadel, "MetaboHc Studies of Rickettsiae. I. The 
Effects of Antimicrobial Substances and Enzyme Inhibitors on the Oxidation 
of Glutamate by Purified Rickettsiae," /. Immunol. 67 (i95i):i23-36; 

A. Karp, "An Immunological Purification of Typhus Rickettsiae," Journal of 
Bacteriology 6j (i954):450-55; C. L. Wisseman, Jr., F. E. Hahn, E. B.Jackson, 
F. M. Bozeman, and J. E. Smadel, "Metabolic Studies of Rickettsiae. II. Studies 
on the Pathway of Glutamate Oxidation by Purified Suspensions of Rickettsia 
mooseri,'' J. Immunol. 68 (19 5 2): 25 1-64; R. A. Ormsbee and M. G. Peacock, 
"Metabolic Activity in Coxiella burnetii,'' J. Bacteriol. 88 (i964):i205-io; 
M. R. Bovarnick and J. C. Miller, "Oxidation and Transamination of Glu- 
tamate by Typhus Rickettsiae," Journal of Biological Chemistry 184 
(i95o):66i— 76; M. R. Bovarnick, "Phosphorylation Accompanying the Ox- 
idation of Glutamate by the Madrid E Strain of Typhus Rickettsiae," /. Biol. 
Chem. 220 (i956):353-6i; D. Paretsky, C. M. Downs, R. A. Consigli, and 

B. K. Joyce, "Studies on the Physiology of Rickettsiae. I. Some Enzyme Systems 
of Coxiella burnetii,'' J. Inf. Dis. 103 (i958):6-ii. 

49. Z. A. Cohn, F. M. Bozeman, J. M. Campbell, J. W. Humphries, and 
T. K. Sawyer, "Study on the Growth of Rickettsiae. V. Penetration of Rickettsia 
tsutsugamushi into Mammalian Cells in Vitro,"/. Exp. Med. 109 (i959):27i- 
92; H. H. Winkler and E. T. Miller, "Immediate Cytotoxicity and Phospho- 
lipase A: The Role of Phospholipase A in the Interaction of R. prowazekii 
and L-Cells," in Burgdorfer and Anacker, eds., Rickettsiae and Rickettsial 
Diseases, 327-33. 

50. M. Schaecter, F. M. Bozeman, and J. E. Smadel, "Study on the Growth 
of Rickettsiae. II. Morphologic Observations of Living Rickettsiae in Tissue 
Culture Cells," Virology 3 (1957): 160-72; C. L. Wisseman, Jr., E. A. Edlinger, 
A. D. Waddell, and M. R. Jones, "Infection Cycle of Rickettsia rickettsii in 
Chicken Embryo and L-929 Cells in Culture," Infect. Immun. 14 (1976): 1052- 
64; D. H. Walker and B. G. Cain, "The Rickettsial Plaque: Evidence for Direct 
Cytopathic Effect of Rickettsia rickettsii," Laboratory Investigation 43 
(i98o):388-96; D. J. Silverman, C. L. Wisseman, Jr., and A. Waddell, "En- 
velopment and Escape of Rickettsia rickettsii from Host Membranes," in 
Burgdorfer and Anacker, eds., Rickettsiae and Rickettsial Diseases, 241—53; 
D. H. Walker, W. T. Firth, and C. S. Edgell, "Human Endothelial Cell Culture 
Plaques Induced by Rickettsia rickettsii," Infect. Immun. 37 (i982):3oi— 6. 
In contrast to the spotted fever organism, R. prowazekii, the agent of epidemic 
typhus, was shown to be released only by bursting the host cell after massive 
intracellular accumulation. See C. L. Wisseman, Jr., and A. D. Waddell, "/« 
Vitro Studies of Rickettsia-Host Cell Interactions: Intracellular Growth Cycle 
of Virulent and Attenuated Rickettsia prowazekii in Chicken Embryo Cells 
in SUde Chamber Cultures," Infect. Immun. 11 (i975):i39i— 1401. 

51. R. A. Ormsbee, "Rickettsiae (as Organisms)," Ann. Rev. Microbiol. 23 
(i969):275-92 (quotation from p. 287); Wisseman, "Some Biological Prop- 
erties of Rickettsiae Pathogenic for Man," 293-311 (quotations from p. 293). 

52. The perception that rickettsial diseases posed no threat doubtless con- 
tributed to this, for young researchers were drawn to areas viewed as pressing 
problems. As early as 1957, Joseph E. Smadel had remarked that, barring 



Notes to Pages 2^2-^4 



335 



atomic warfare, the rickettsial diseases in the United States "really presented 
no serious problems." See J. E. Smadel, "Remarks of Director, Commission 
on Rickettsial Diseases, at semiannual meeting of Armed Forces Epidemio- 
logical Board," 9 December 1957, copy in NIAID Public Information Office. 

53. Minutes of Meeting of Board of Scientific Counselors, National Institute 
of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 
Maryland, 7 and 8 December 1967, RML Director's Files (see chap. 8, n. 60). 
Although no specific attribution for this remark is given in the minutes, the 
speaker was probably the scientific director of NIAID, John R. Seal. 

54. R. A. Ormsbee, in "Rickettsial Diseases— A Public Health Problem?" 
/. Inf. Dis. 127 (i973):325-27, noted only two rickettsial grants in 1971. In 
U.S., National Institutes of Health, Division of Research Grants, Research 
Grants Index, Fiscal Year 1971 (Washington, D.C.: Government Printing 
Office, [1972]), I found five that might be considered rickettsial grants, al- 
though that classification could be disputed depending upon the emphasis of 
the study. 

55. Charles L. Wisseman, Jr., personal communication to the author, 24 
March 1988; T. E. Woodward, "A Historical Account of the Rickettsial Dis- 
eases with a Discussion of Unsolved Problems," /. Inf. Dis. izj (i973):583- 
94 (quotations from p. 593); Ormsbee, "Rickettsial Diseases— A Public Health 
Problem?" 326. 

56. J. R. Seal, "The United States Public Health Service and Rickettsial 
Diseases, Past, Present, Future," in Burgdorfer and Anacker, eds., Rickettsiae 
and Rickettsial Diseases, 6. 

57. My discussion of this debate is based on ibid., 6; Minutes of the Meetings 
of the Board of Scientific Counselors of the National Institute of Allergy and 
Infectious Diseases, 1955-1981, and numerous interviews with scientists and 
administrators at NIAID. The minutes are held by the institute in Bethesda, 
Maryland, and in Hamilton, Montana; the interviews are in the NIAID files, 
NIH Historical Office. 

58. The acrimony generated by this debate reflects how difficult the process 
of reaching consensus about research priorities can be. Since the late 1970s, 
when NIAID discontinued support for medical entomology, the number of 
medical entomologists in the United States has continued to dwindle, as wit- 
nessed by a May 1988 policy paper in Science on the dangers of losing com- 
petence in arthropod systematics. See J. H. Oliver, Jr., "Crisis in Biosystematics 
of Arthropods," Science 240 (i988):967. Lists of grants and contracts for 
rickettsial research may be obtained from the Division of Research Grants, 
National Institutes of Health, Bethesda, Maryland. Those for 1979 are listed 
in Burgdorfer and Anacker, eds., Rickettsiae and Rickettsial Diseases, 7-8. 
Acknowledgements of support from NIAID are listed in most of the published 
papers in the field. 

59. Ormsbee, "Rickettsial Diseases— A Public Health Problem?" 326-27. 
Richard A. Ormsbee noted in a personal communication to the author, 25 
February 1988, that the eastern bloc rickettsial research program, especially 
on Q fever, was stimulated during the late 1960s by the Slovak Academy of 
Sciences, particularly by D. Blaskovii. Three researchers fromi his Laboratory 
of Virology in Bratislava — Rudolf Brezina, Jan Kazan, and Steve Schramek- 
were permitted by the Czechoslovak authorities to visit the RML, the U.S. 
Naval Medical Research Laboratories, and the University of Maryland School 
of Medicine to study rickettsial research methods. 



33^ 



Notes to Pages 2,3^-^8 



60. Smadel, "Status of the Rickettsioses in the United States," 424; E. L. 
Atwood, J. T. Lamb, R. Sonnenshine, and D. E. Sonnenshine, "A Contribution 
to the Epidemiology of Rocky Mountain Spotted Fever in the Eastern United 
States," Am. J. Trop. Med. Hyg. 14 (1965): 83 1-37; M. A. W. Hattwick, 
"Rocky Mountain Spotted Fever in the United States, 19 20-1 970," /. Inf. 
Dis. 124 (1971):! 1 2-14; L. J. D'Angelo, W. G. Winkler, and D. J. Bregman, 
"Rocky Mountain Spotted Fever in the United States, 197 5-1 977," /. Inf. 
Dis. 138 (1978): 273-76. This increase merited attention in the British Medical 
Journal, even though spotted fever did not occur in the British Isles. See "Rocky 
Mountain Spotted Fever," British Medical Journal 2 (i978):65i. 

61. M. A. W. Hattwick, R. J. O'Brien, and B. F. Hanson, "Rocky Mountain 
Spotted Fever: Epidemiology of an Increasing Problem," Ann. Int. Med. 84 

(1976) :732-39. 

62. W. Burgdorfer, "Tick-Borne Diseases in the United States: Rocky Moun- 
tain Spotted Fever and Colorado Tick Fever: A Review," Acta Tropica 34 

(1977) :i03-26 (quotations from pp. 113-14). 

63. The reasons for women's apparent advantage in resisting spotted fever 
remain an unexplored area of research. David H. Walker noted in a personal 
communication to the author, 30 November 1988, that "questions of host 
defenses and resistance seem to be key to understanding differences in mor- 
bidity and mortality among different individuals." 

64. Hattwick, O'Brien, and Hanson, "Rocky Mountain Spotted Fever: Ep- 
idemiology of an Increasing Problem," 738. 

65. "Rocky Mountain Spotted Fever— United States, 1985," JAMA 255 
(i986):286i, 2867; D. B. Fishbein, J. E. Kaplan, K. W. Bernard, and W. G. 
Winkler, "Surveillance of Rocky Mountain Spotted Fever, United States, 198 1- 
1983," Morbidity and Mortality Weekly Report, CDC Surveillance Summaries 
33 (i984):i5SS-i8SS. In 1983 a group from the Butantan Institute in Sao 
Paulo, Brazil, noted that a presumptive case of spotted fever had been reported 
in 1979 but that accurate information was not available for the country as a 
whole. See D. A. Portari Mancini, E. M. Mendes Nascimento, V. Rosa Tavares, 
and M. Adelino Soares, "A ocorrencia de riquetsioses do grupo Rickettsia 
rickettsii,'' Revista de Saude publica 17 (i983):493— 99. 

66. V. Scaffidi, "Attuale espansione endemo-epidemica della febre bottonosa 
in Italia," Minerva Medica 72 (i98i):2o63-70 (quotations from Eng. sum- 
mary). 

67. A. Gutman, H. Schreiber, and R. Taragan, "An Outbreak of Tick Typhus 
in the Coastal Plain of Israel: 13 Cases from the Sharon Area," Trans. Royal 
Soc. Trop. Med. Hyg. 67 (i973):ii2-2i; H. Schulchynska, R. Dagan, 
F. Schlaefer, and A. Keynan, "Spotted Fever in the Negev," Harefuah 102 
(1982): 3 17-19 (in Hebrew with Eng. summary); V. Scaffidi, "Contempora- 
neita della recente espansione endemo-epidemica della febbre bottonosa in 
Italia ed in Israele," Giornale diMalattie Infettive e Parassitarie 34 ( 198 2): 677- 
81. 

68. F. Segura and B. Font, "Resurgence of Mediterranean Spotted Fever in 
Spain," Lancet 2 (i982):28o. 

69. For citations to this work, see the bibliography in D. H. Walker, J. I. 
Herrero-Herrero, R. R. Beltran, A. Bullon-Sopelana, and A. Ramos-Hidalgo, 
"The Pathology of Fatal Mediterranean Spotted Fever," American Journal of 
Clinical Pathology 87 (i987):669-72. 



Notes to Pages 2^8-41 



337 



70. S. Mansueto, G. Vitale, M. D. Miceli, G. Tringlai, P. Quartararo, 
D. M. Picone, and C. Occhino, "A Sero-epidemiological Survey of Asymp- 
tomatic Cases of Boutonneuse Fever in Western Sicily," Trans. Royal Soc. 
Trop. Med. Hyg. 78 (1984): 16-18; S. Mansueto, G. Vitale, M. Bentivegna, 

G. Tringali, and R. DiLeo, "Persistence of Antibodies to Rickettsia conorii 
after an Acute Attack of Boutonneuse Fever,"/. Inf. Dis. 151 (i985):377. For 
research on the role of dogs in tick-borne rickettsioses, see W. W. C. Topley 
and G. S. Wilson, The Principles of Bacteriology and Immunity, 2d ed. (Bal- 
timore: WiUiam Wood &c Co., 1936), 1461; L. F. Badger, "Rocky Mountain 
Spotted Fever: Susceptibility of Dog and Sheep to Virus," Pub. Health Rep. 

48 (i933):79i-95; C. C. Shepard and N. H. Topping, "Rocky Mountain 
Spotted Fever: A Study of Complement Fixation in the Serum of Certain Dogs," 
/. Inf Dis. 78 (i946):63-68; K. P. Keenan, W C. Buhles, Jr., D. L. Huxsoll, 
R. G. Williams, P. K. Hildebrandt, J. M. Campbell, and E. H. Stephenson, 
"Pathogenesis of Infection w^ith Rickettsia rickettsii in the Dog: A Disease 
Model for Rocky Mountain Spotted Fever,"/. Inf. Dis. 135 (i977):9ii-i7; 
S. Mansueto and G. Vitale, "Antibodies to Rickettsia conorii in Dogs in 
Western Sicily," Trans. Royal Soc. Trop. Med. Hyg. 78 (i984):68i-82; G. 
TringaH, V. Intonazzo, A. M. Perna, S. Mansueto, G. Vitale, and D. H. Walker, 
"Epidemiology of Boutonneuse Fever in Western Sicily: Distribution and Prev- 
alence of Spotted Fever Group Rickettsial Infection in Dog Ticks [Rhipice- 
phalus sanguineus),'' Am. J. Epidemiol. 123 (i986):72i-27; E. B. Breit- 
schwerdt, D. H. Walker, M. G. Levy, W. Burgdorfer, W. T Corbett, S. A. 
Hurlbert, M. E. Stebbins, B. C. Curtis, and D. A. Allen, "Clinical Hematologic, 
and Humoral Immune Response in Female Dogs Inoculated with Rickettsia 
rickettsii and Rickettsia montana,"" American Journal of Veterinary Research 

49 (i988):70-76. 

71. Centers for Disease Control, "Fatal Rocky Mountain Spotted Fever— 
Georgia," Morbidity and Mortality Weekly Report 26 (1977): 84; "Spotted 
Fever Kills 2 at Disease Center," n.d., clipping in personal scrapbook of David 
B. Lackman, Helena, Montana, copy in NIAID files, NIH Historical Office. 

72. In 1979 a group of rickettsiologists met at Fort Deposit, Maryland, to 
discuss formation of a new professional group. The American Society of 
Rickettsiology and Rickettsial Diseases was officially organized in 1980 at a 
meeting held at the RML. I am grateful to David H. Walker for providing 
information about the evolution of this organization. 

Chapter Twelve: Mysteries Explained, Mysteries Remaining 

1. Dowling, Fighting Infection (see chap. 10, n. 24), 248. 

2. Florman and Hafkenschiel, "The Eastern Variety of Rocky Mountain 
Spotted Fever" (see chap. 8, n. 41), 123-33; J. T. Aquilina, F. Rosenberg, and 
R. L. Wuertz, "Nodal Tachycardia in a Case of Rocky Mountain Spotted 
Fever," American Heart Journal 43 (i952):755-6o; J. K. Aikawa and G. T. 
Harrell, "Effect of Cortisone Acetate on Experimental Rocky Mountain Spot- 
ted Fever in the Guinea Pig," Proc. Soc. Exp. Biol. Med. 82 (i953):698-70i; 

H. S. Moore, "Electrocardiograms in Tick Typhus," East African Med. J. 40 
(i963):6i8-22; C. W Phillips, G. T. Kimbrough, J. A. Weaver, and A. L. 
Tucker, "Rocky Mountain Spotted Fever with Thrombocytopenia," Southern 
Med. J. 53 (i960): 867-69; C. E. Mengel and C. Trygstad, "Thrombocytopenia 



338 



Notes to Pages 241-42 



in Rocky Mountain Spotted Fever," JAMA 183 (i963):886; J. W. Trigg, Jr., 
"Hypofibrinogenemia in Rocky Mountain Spotted Fever," New England J. 
Med. 270 (1964): 1042— 44; W. D. Bradford and D. B. Hackel, "Myocardial 
Involvement in Rocky Mountain Spotted Fever," Arch. Pathol. Lab. Med. 102 
(1978): 3 57-59; D. H. Walker, C. E. Paletta, and B. G. Cain, "Pathogenesis 
of Myocarditis in Rocky Mountain Spotted Fever," Arch. Pathol. Lab. Med. 
104 (i98o):i7i-74. 

3. Louis Berlin, "Rocky Mountain Spotted Fever," letter to the editor and 
response, /v4Mi4 134 (1947): 15 80. 

4. Major studies on spotted fever's neurological manifestations include 
G. B. Hassin, "Cerebral Changes in Rocky Mountain Spotted Fever," Archives 
of Neurology and Psychiatry 44 (1940): 1290-95; M. Scheinker, "Histologic 
Observations on the Changes in the Brain in Rocky Mountain Spotted Fever," 
Arch. Pathol. 35 (1943): 5 83— 89; "Neurologic Sequelae of Rocky Mountain 
Spotted Fever," abstract in JAMA 141 (1949): 1017; R. E. Haynes, D. Y. 
Sanders, and H. G. Cramblett, "Rocky Mountain Spotted Fever in Children," 
/. Pediatrics 76 (i97o):685— 93; and E. W. Massey, T. Thamse, C. E. Coffey, 
and H. A. Gallis, "Neurologic Complications of Rocky Mountain Spotted 
Fever," South. Med. J. 78 (i985):i288-90, 1303. 

5. M. J. Rosenblum, R. L. Masland, and G. T. Harrell, "Residual Effects 
of Rickettsial Disease on the Central Nervous System: Results of Neurologic 
Examinations and Electroencephalograms Following Rocky Mountain Spotted 
Fever," Arch. Int. Med. 90 (19 5 2) 1444-5 5 (quotation from p. 444). 

6. A. E. Davis, Jr., and W. D. Bradford, "Abdominal Pain Resembling Acute 
Appendicitis in Rocky Mountain Spotted Fever," JAMA 247 (1982): 28 11- 
12. See also M. B. Randall and D. H. Walker, "Rocky Mountain Spotted 
Fever: Gastrointestinal and Pancreatic Lesions and Rickettsial Infection," Arch. 
Pathol. Lab. Med. 108 (i984):963-67; D. H. Walker, H. R. Lesesne, V. A. 
Varma, and W. C. Thacker, "Rocky Mountain Spotted Fever Mimicking Acute 
Cholecystitis," Arch. Int. Med. 145 (i985):2i94-96. 

7. D. H. Walker, "Rickettsial Diseases: An Update," in Guido Majno, Ramzi 
S. Cotran, and Nathan Kaufman, eds.. Current Topics in Inflammation and 
Infection, International Academy of Pathology, Monographs in Pathology no. 
23 (Baltimore: Williams &; Wilkins, 1982), 188-204. 

8. G. T. Harrell, "Rocky Mountain Spotted Fever," Medicine 28 (i949):333- 
69; Jerry K. Aikawa, Rocky Mountain Spotted Fever (Springfield, 111.: Charles 
C. Thomas, 1966). The bibliography in Aikawa's book contains most citations 
to the large body of studies conducted by Harrell, Aikawa, and their colleagues. 
Aikawa suggested that the disease should be called rickettsial spotted fever. 
See p. 118. 

9. D. H. Walker, H. N. Kirkman, and R H. Wittenberg, "Genetic States 
Possibly Associated with Enhanced Severity of Rocky Mountain Spotted Fe- 
ver," in Burgdorfer and Anacker, eds., Rickettsiae and Rickettsial Diseases 
(see chap. 9, n. 14), 621-30 (quotation from p. 629); D. H. Walker, H. K. 
Hawkins, and P. Hudson, "Fulminant Rocky Mountain Spotted Fever: Its 
Pathologic Characteristics Associated with Glucose-6-Phosphate Dehydro- 
genase Deficiency," Arch. Pathol. Lab. Med. 107 (i983):i2i-25. Glucose-6- 
phosphate dehydrogenase deficiency is a genetic condition that apparently 
evolved like the sickle-cell trait by providing its carriers with some protection 
against malaria. See Kimberly Weiss, "The Role of Rickettsioses in History," 



Notes to Pages 242-4 j 



339 



in David H. Walker, ed., Biology of Rickettsial Diseases, 2 vols. (Boca Raton, 
Fla.: CRC Press, 1988), 1:12-13. 

10. T. H. Maugh II, "Rickettsiae: A New Vaccine for Rocky Mountain 
Spotted Fever," Science 201 (1978): 604. 

11. L. J. D'Angelo and W. G. Winkler, "Rocky Mountain Spotted Fever," 
New England J. Med. 298 (1978): 54; J. E. Johnson III, and R J. Kadull, 
"Rocky Mountain Spotted Fever Acquired in a Laboratory," ibid. 277 
(i967):842-47; R M. Calia, R J. Bartelloni, and R. W. McKinney, "Rocky 
Mountain Spotted Fever: Laboratory Infection in a Vaccinated Individual," 
JAMA 211 (i97o):20i2-i4; D. J. Sexton, H. A. Gallis, J. R. McRae, and 
T. R. Gate, "Possible Needle-Associated Rocky Mountain Spotted Fever," New 
England J. Med. 191 (i975):645; G. N. Oster, D. S. Burke, R. H. Kenyon, 
M. S. Ascher, P. Harber, and G. E. Pedersen, Jr., "Laboratory-Acquired Rocky 
Mountain Spotted Fever: The Hazard of Aerosol Transmission," New England 
J. Med. 297 (i977):859-63. 

12. H. L. DuPont, R. B. Hornick, A. T. Dawkins, G. G. Heiner, I. B. 
Fabrikant, G. L. Wisseman, Jr., and T. E. Woodward, "Rocky Mountain 
Spotted Fever: A Gomparative Study of the Active Immunity Induced by 
Inactivated and Viable Pathogenic Rickettsia rickettsii,'' J. Inf. Dis. 128 
(i973):340-44. 

13. R. R. Parker and E. A. Steinhaus, "Rocky Mountain Spotted Fever: 
Duration of Potency of Tick-Tissue Vaccine," Pub. Health Rep. 58 
(i943):23o— 32; "Minimum Requirements: Rocky Mountain Spotted Fever 
Vaccine Prepared from Infected Membranes of the Embryonated Ghicken Egg," 
mimeo., National Institute of Health, Bethesda, Maryland, 13 August 1945; 
D. B. Lackman and R. R. Parker, "Gomparison of the Immunogenic and 
Anaphylactogenic Properties of Rocky Mountain Spotted Fever Vaccines Pre- 
pared from Infected Yolk Sacs and from Infected Tick Tissue," Am. J. Pub. 
Health 38 (i948):i402— 4; E. J. Bell and H. G. Stoenner, "Spotted Fever 
Vaccine: Potency Assay by Direct Ghallenge of Vaccinated Mice with Toxin 
of Rickettsia rickettsii,''' ]. Immunol. 87 (i96i):737-46. 

14. R. H. Kenyon, W. M. Acree, G. G. Wright, and E W Melchoir, Jr., 
"Preparation of Vaccines for Rocky Mountain Spotted Fever from Rickettsiae 
Propagated in Gell Gulture," /. Inf. Dis. 125 (i972):i46-52; R. H. Kenyon 
and G. E. Pedersen, Jr., "Preparation of Rocky Mountain Spotted Fever Vaccine 
Suitable for Human Immunization," Journal of Clinical Microbiology i 
(1975): 500— 503; R. H. Kenyon, L. St. G. Sammons, and G. E. Pedersen, 
"Gomparison of Three Rocky Mountain Spotted Fever Vaccines," /. Clin. 
Microbiol. 2 (1975): 300-304; M. S. Ascher, G. N. Oster, P. I. Harber, R. H. 
Kenyon, and G. E. Pedersen, "Initial Glinical Evaluation of a New Rocky 
Mountain Spotted Fever Vaccine of Tissue Gulture Origin," /. Inf. Dis. 138 
(i978):2i7-2i. 

15. Augerson to Krause, 9 November 1976, cited in Robert Edelman, chief, 
Glinical Studies Branch, Microbiology and Infectious Diseases Program, Na- 
tional Institute of Allergy and Infectious Diseases, to Deputy Director, NIAID, 
memorandum, 16 November 1976, file "RMSF," files of the Microbiology 
and Infectious Diseases Program, NIAID (hereafter cited as MIDP files, 
NIAID). 

16. "Rocky Mountain Spotted Fever in Ghildren: The Gase for Immuni- 
zation," remarks by Samuel L. Katz, M.D., to the Microbiology and Infectious 



340 



Notes to Pages 14^-48 



Diseases Advisory Committee of the National Institute of Allergy and Infec- 
tious Diseases, 30 October 1978, file "RMSF— Volunteer Study," MIDP files, 
MAID. 

17. Chief, Development and Applications Branch, MIDP, NIAID, to Ex- 
ecutive Officer, NIAID, draft memorandum, 14 November 1978, file "RMSF," 
MIDP files, NIAID. 

18. John R. Seal, NIAID deputy director, to Director, MIDP, memorandum, 
25 April 1979, file "RMSF -Volunteer Study," MIDP files, NIAID. The U.S. 
Food and Drug Administration regulates the procedures under w^hich inves- 
tigational new drugs are developed and tested. The process is explained in lay 
terminology in U.S. Food and Drug Administration, From Test Tube to Patient: 
New Drug Development in the United States, an FDA Consumer special report, 
HHS Publication no. (FDA) 88-3168 (Washington, D.C., 1988). 

19. C. M. Wilfert, E. Austm, V. Dickinson, K. Kleeman, J. L. Hicks, J. N. 
MacCormack, R. L. Anacker, E. A. Casper, and R. N. Philip, "The Incidence 
of Rocky Mountain Spotted Fever as Described by Prospective Epidemiologic 
Survelliance and the Assessment of Persistence of Antibodies to R. rickettsii 
by Indirect Hemagglutination and Microimmunofluorescence Tests," in Burg- 
dorfer and Anacker, eds., Rickettsiae and Rickettsial Diseases, ly^—S^-, J. D. 
Folds, D. H. Walker, B. C. Hegarty, D. Banasiak, and J. V. Lange, "Rocky 
Mountain Spotted Fever Vaccine in an Animal Model," /. Clin. Microbiol. 18 
(i983):32i-26. 

20. M. L. Clements, C. L. Wisseman, Jr., T. E. Woodw^ard, P. Fiset, J. S. 
Dumler, W. McNamee, R. E. Black, J. Rooney, T. P. Hughes, and M. M. 
Levine, "Reactogenicity, Immunogenicity, and Efficacy of a Chick Embryo 
Cell-Derived Vaccine for Rocky Mountain Spotted Fever," /. Inf. Dis. 148 
(i983):922-30 (quotation from p. 922). 

21. U.S. Department of Health, Education, and Welfare, Food and Drug 
Administration, "Review^ of Rocky Mountain Spotted Fever (RMSF) Vaccine," 
pp. 25736—37 in "Viral and Rickettsial Vaccines: Proposed Implementation 
of Efficacy Review," Federal Register 45 (i98o):25652— 25758. 

22. Ibid., 25737; DuPont et al., "Rocky Mountain Spotted Fever: A Com- 
parative Study," 343; Clements et al., "Reactogenicity, Immunogenicity, and 
Efficacy," 929. 

23. My discussion of this follows Tortora, Funke, and Case, Microbiology: 
An Introduction (see chap. 11, n. 47), 438. See also D. H. Walker and F, W. 
Henderson, "Effect of Immunosuppression on Rickettsia rickettsii Infection 
in Guinea Pigs," Infect. Immun. 20 (i978):22i-27; R. H. Kenyon and C. E. 
Pedersen, Jr., "Immune Responses to Rickettsia akari Infection in Congenitally 
Athymic Nude Mice," Infect. Immun. 28 (i98o):3io-i3; L. N. Kokorin, E. 
A. Kabanova, E. A. Shirokova, G. E. Abrosimova, N. N. Rybkina, and V. I. 
Pushkareva, "Role of T-Lymphocytes in Rickettsia conorii infection," Acta 
Virol. 26 (i982):9i-97; Han Li, T. R. Jerrells, G. L. Spitalny, and D. H. 
Walker, "Gamma Interferon as a Crucial Host Defense Against Rickettsia 
conorii in Vivo," Infect. Immun. 55 (1987): 125 2-5 5. 

24. For an overview and bibliography of recent work on rickettsial vaccines 
see D. H. Walker, "Role of the Composition of Rickettsiae in Rickettsial 
Immunity: Typhus and Spotted Fever Groups," in Walker, ed.. Biology of 
Rickettsial Diseases 2:101—9. 

25. Hui Min Feng, C. Kirkman, and D. H. Walker, "Radioimmunoprecip- 
itation of [P^S] Methionine-Radiolabeled Proteins of Rickettsia conorii and 



Notes to Pages 248-^0 



341 



Rickettsia rickettsii,'" J. Inf. Dis. 154 {-l^^6):j ij— 2.1 (quotation from p. 717); 
R. L. Anacker, R. N. Philip, J. C. Williams, R. H. List, R. E. Mann, "Bio- 
chemical and Immunochemical Analysis of Rickettsia rickettsii Strains of Var- 
ious Degrees of Virulence," Infect. Immun. 44 (1984): 5 59-64; J. V. Lange 
and D. H. Walker, "Production and Characterization of Monoclonal Anti- 
bodies to Rickettsia rickettsii,'' Infect. Immun. 46 (i984):289-94; R. L. An- 
acker, R. H. List, R. E. Mann, S. F. Hayes, and L. A. Thomas, "Characterization 
of Monoclonal Antibodies Protecting Mice against Rickettsia rickettsii,'" 
J. Inf. Dis. 151 (198 5): 105 2-60; R. L. Anacker, R. H. List, R. E. Mann, and 
D. L. Wiedbrauk, "Antigenic Heterogeneity in High- and Low-virulence Strains 
of Rickettsia rickettsii Revealed by Monoclonal Antibodies," Infect. Immun. 
51 (i986):653-6o; D. H. Walker, P. Hanff, and B. Hegarty, "Analysis of 
Protein Antigens of Rickettsia rickettsii and Rickettsia conorii by Western 
Immunoblotting," in J. J. Kazar, ed., Rickettsiae and Rickettsial Diseases: 
Proceedings of the Ilird International Symposium (Bratislava: Publishing 
House of the Slovak Academy of Sciences, 1985), 92-98; J. C. WiUiams, 
D. H. Walker, M. G. Peacock, S. T. Stewart, "Humoral Immune Response to 
Rocky Mountain Spotted Fever in Experimentally Infected Guinea Pigs: Im- 
munoprecipitation of Lactoperoxidase ^^^I-labeled Proteins and Detection of 
Soluble Antigens of Rickettsia rickettsii,'' Infect. Immun. 52 (i986):i2o— 27; 
H. M. Feng, D. H. Walker, and J. G. Wang, "Analysis of T-Cell-Dependent 
and -Independent Antigens of Rickettsia cowonV with Monoclonal Antibodies," 
Infect. Immun. 55 (i987):7-i5; H. Li, B. Lenz, and D. H. Walker, "Protective 
Monoclonal Antibodies Recognize Heat-Labile Epitopes on Surface Proteins 
of Spotted Fever Group Rickettsiae," Infect. Immun. 56 (1988): 25 87-93; 
Robert L. Anacker, interview by Victoria A. Harden, Hamilton, Montana, 26 
October 1984, NIAID Files, NIH Historical Office. 

26. G. A. McDonald, R. L. Anacker, and K. Garjian, "Cloned Gene of 
Rickettsia rickettsii Surface Antigen: Candidate Vaccine for Rocky Mountain 
Spotted Fever," Science 235 (i987):83-84. 

27. C. C. Shepard, M. A. Redus, T. Tzianabos, and D. T. Warfield, "Recent 
Experience with the Complement Fixation Test in the Laboratory Diagnosis 
of Rickettsial Diseases in the United States,"/. Clin. Microbiol. 4 (i976):277— 
83 (quotation from p. 283). 

28. M. A. W Hattwick, H. Retailliau, R. J. O'Brien, M. Slutzker, R. E. 
Fontaine, and B. Hanson, "Fatal Rocky Mountain Spotted Fever," JAMA 240 
(1978): 1499— 1503 (quotation from p. 1502). 

29. For a survey of the most recent methods of laboratory diagnosis, see 
D. H. Walker and M. G. Peacock, "Laboratory Diagnosis of Rickettsial Dis- 
eases," in Walker, ed.. Biology of Rickettsial Diseases, 2:135-55. 

30. S. Chang, "A Serologically Active Erythrocyte-Sensitizing Substance 
from Typhus Rickettsiae. I. Isolation and Titration," /. Immunol. 70 
(i953):2i2— 14; S. Chang, J. C. Snyder, and E. S. Murray, "A Serologically 
Active Erythrocyte-Sensitizing Substance from Typhus Rickettsiae. II. Sero- 
logical Properties," ibid., 215—21; S. Chang, E. S. Murray, and J. C. Snyder, 
"Erythrocyte-Sensitizing Substances from Rickettsiae of the Rocky Mountain 
Spotted Fever Group," ibid. 73 (i954):8-i5; D. M. Hersey, M. C. Clovin, 
and C. C. Shepard, "Studies on the Serologic Diagnosis of Murine Typhus 
and Rocky Mountain Spotted Fever. II. Human Infections," ibid. 79 
(i957):409-i5. 



34^ 



Notes to Pages 



31. A. Shirai, J. W. Dietel, and J. V. Osterman, "Indirect Hemagglutination 
Test for Human Antibody to Typhus and Spotted Fever Group Rickettsiae," 
/. Clin. Microbiol. 1 (i975):430-37; R. L. Anacker, R. K. Gerloff, L. A. 
Thomas, R. E. Mann, W. R. Brown, and W. D. Bickel, "Purification of Rick- 
ettsia rickettsii by Density-Gradient Zonal Centrifugation," Canadian Journal 
of Microbiology 20 (i974):i523-27; R. L. Anacker, R. K. Gerloff, L. A. 
Thomas, R. E. Mann, and W. D. Bickel, "Immunological Properties of Rick- 
ettsia rickettsii Purified by Zonal Centrifugation," Infect. Immun. 11 

(1975) : 1203-9; R. L. Anacker, R. N. Philip, L. A. Thomas, and E. A. Casper, 
"Indirect Hemagglutination Test for Detection of Antibody to Rickettsia rick- 
ettsii in Sera from Humans and Common Laboratory Animals," /. Clin. Mi- 
crobiol. 10 (i979):677— 84. 

32. P. Fiset, R. A. Ormsbee, R. Silberman, M. Peacock, and S. H. Spielman, 
"A Microagglutination Technique for Detection and Measurement of Rick- 
ettsial Antibodies," Acta Virol. 13 (1969)160-66; K. E. Hechemy, R. W. 
Stevens, and H. A. Gaafar, "Detection of Escherichia coli Antigens by a Latex 
Agglutination Test," Applied Microbiology 28 ( 1974): 306-1 1; K. E. Hechemy, 
R. W. Stevens, J. Sroka and H. A. Gaafar, "Latex Test for Quantitative De- 
termination of Escherichia coli Antibody," Applied Microbiol. 28 
(1974): 1073-75; K. E. Hechemy, R. W. Stevens, and H. A. Gaafar, "Antigen 
Distribution in a Latex Suspension and Its Relationship to Test Sensitivity," 
/. Clin. Microbiol. 4 (i976):82-86; K. E. Hechemy, R. L. Anacker, R. N. 
Philip, K. T. Kleeman, J. N. McCormack, S. J. Sasowski, and E. E. Michaelson, 
"Detection of Rocky Mountain Spotted Fever Antibodies by a Latex Agglu- 
tination Test,"/. Clin. Microbiol. 12 (i98o):i44— 50. 

33. A. H. Coons, J. C. Snyder, F. S. Cheevers, and E. S. Murray, "Localization 
of Antigen in Tissue Cells. IV. Antigens of Rickettsiae and Mumps Virus," 
/. Exp. Med. 91 (i95o):3i-37; W. Burgdorfer and D. B. Lackman, "Identi- 
fication of Rickettsia rickettsii in the Wood Tick, Dermacentor andersoni, by 
Means of Fluorescent Antibody," /. Inf. Dis. 107 (i96o):24i-44; W. Burg- 
dorfer, "Evaluation of the Fluorescent Antibody Technique for the Detection 
of Rocky Mountain Spotted Fever Rickettsiae in Various Tissues," Pathologie 
et Microbiologia 24 (i96i):27-39. 

34. C. E. Pedersen, Jr., L. R. Bagley, R. H. Kenyon, L. S. Sammons, and 
G. T. Burger, "Demonstration of Rickettsia rickettsii in the Rhesus Monkey 
by Immune Fluorescence Microscopy,"/. Clin. Microbiol. 2 (i975):i2i— 25; 
R. N. Philip, E. A. Casper, R. A. Ormsbee, M. G. Peacock, and W. Burgdorfer, 
"Microimmunofluorescence Test for the Serological Study of Rocky Mountain 
Spotted Fever and Typhus," ibid. 3 (1976): 51-61; R. D. DeShazo,J. R. Boyce, 
J. V. Osterman, and E. H. Stephenson, "Early Diagnosis of Rocky Mountain 
Spotted Fever: Use of Primary Monocyte Culture Technique," JAMA 235 

(1976) : 1 3 53-5 5; D. H. Walker, A. Harrison, F. Henderson, and F. A. Murphy, 
"Identification of Rickettsia rickettsii in a Guinea Pig Model by Immunoflu- 
orescent and Electron Microscopic Techniques," Am. J. Pathol. 86 

(1977) :343— 58; M. L. Clements, J. S. Dumler, Paul Fiset, C. L. Wisseman, 
Jr., M. J. Snyder, and M. M. Levine, "Serodiagnosis of Rocky Mountain 
Spotted Fever: Comparison of IgM and IgG Enzyme-Linked Immunoabsorbent 
Assays and Indirect Fluorescent Antibody Test,"/. Inf. Dis. 148 (i983):876— 
80. 

35. Philip et al., "Comparison of Serologic Methods" (see chap. 9, n. 57); 
V. F. Newhouse, C. C. Shepard, M. D. Redus, T. Tzianabos, and J. E. McDade, 



Notes to Pages 



343 



"A Comparison of the Complement Fixation, Indirect Fluorescent Antibody, 
and Microagglutination Tests for the Serological Diagnosis of Rickettsial Dis- 
eases," Am. J. Trop. Med. Hyg. 28 (1979): 3 87-9 5; K. E. Hechemy, R. L. 
Anacker, N. L. Carlo, J. A. Fox, and H. A. Gaafar, "Absorption of Rickettsia 
rickettsii Antibodies by Rickettsia rickettsii Antigens in Four Diagnostic Tests," 
/. Clin. Microbiol. 17 (i983):445-49. 

36. T. E. Woodward, C. E. Pedersen, Jr., C. N. Oster, L. R. Bagley, 
J. Romberger, and M. J. Snyder, "Prompt Confirmation of Rocky Mountain 
Spotted Fever. Identification of Rickettsiae in Skin Tissues," /. Inf. Dis. 134 
(1976): 297-301; D. H. Walker and B. G. Cain, "A Method for Specific Di- 
agnosis of Rocky Mountain Spotted Fever on Fixed, Paraffin-Embedded Tissue 
by Immunofluorescence," ibid. 137 (i978):2o6-9; D. H. Walker, B. G. Cain, 
and P. M. Olmstead, "Laboratory Diagnosis of Rocky Mountain Spotted Fever 
by Immunofluorescent Demonstration of Rickettsia rickettsii in Cutaneous 
Lesions," Am. J. Clin. Pathol. 69 (i978):6i9-23; W. R. Green, D. H. Walker, 
and B. G. Cain, "Fatal Viscerotropic Rocky Mountain Spotted Fever: Report 
of a Case Diagnosed by Immunofluorescence," American journal of Medicine 
64 (i978):523-28; G. Fleisher, E. T. Lennette, and P. Honig, "Diagnosis of 
Rocky Mountain Spotted Fever by Immunofluorescent Identification of Rick- 
ettsia rickettsii in Skin Biopsy Tissue,"/. Pediatrics 95 (1979): 63-65. 

37. Walker, "Rickettsial Diseases: An Update," 188-204; D. H. Walker, 
R. M. Gay, and M. Valdes-Dapena, "The Occurrence of Eschars in Rocky 
Mountain Spotted Fever," Journal of the American Academy of Dermatology 
4 (i98i):57i-76. 

38. "Virginia Chapter Campaigns against RMSF," Double Helix, newsletter 
of the National Foundation for Infectious Diseases, i (July 1977) :4. 

39. L. J. D'Angelo, D. J. Bregman, and W. G. Winkler, "Rocky Mountain 
Spotted Fever in the United States: Use of Age-Specific Incidence to Determine 
Public Health Policy for a Vector-Borne Disease," Southern Med. J. 75 
(198 2): 3-5; Willy Burgdorfer, interview by Victoria A. Harden, Hamilton, 
Montana, 22 October 1984, NIAID files, NIH Historical Office (hereafter 
cited as Burgdorfer interview). 

40. J. K. Miller, "Rocky Mountain Spotted Fever on Long Island," Ann. 
Int. Med. 33 (1950): 1398— 1406; W. Burgdorfer, "Hemolymph Test: A Tech- 
nique for Detection of Rickettsiae in Ticks," Am. J. Trop. Med. Hyg. 19 
(i97o):ioio-i4. 

41. Quotations from Burgdorfer interview. Major papers growing out of 
this investigation were: W. Burgdorfer, A. G. Barbour, S. F. Hayes, J. L. Benach, 
E. Grunwaldt, and J. P. Davis, "Lyme Disease— A Tick-Borne Spirochetosis?" 
Science 216 (1982): 13 17-19; E. M. Bosler, J. L. Coleman, J. L. Benach, 
D. A. Massey, J. P. Hanrahan, W. Burgdorfer, and A. G. Barbour, "Natural 
Distribution of the Ixodes dammini Spirochete," ibid. 220 (i983):32i-22; 
W. Burgdorfer and J. E. Kerians, "Ticks and Lyme Disease in the United 
States," Ann. Int. Med. 99 (1983): 121; A. C. Steere, R. L. Grodzicki, A. N. 
Kornblatt, J. E. Craft, A. G. Barbour, W. Burgdorfer, G. P. Schmid, E. Johnson, 
and S. E. Malawista, "The Spirochetal Etiology of Lyme Disease," New Eng- 
land J. Med. 308 (i983):733-4o; J. L. Benach, E. M. Bosler, J. P. Hanrahan, 
J. L. Coleman, G. S. Habicht, T. F. Bast, D. J. Cameron, J. L. Ziegler, A. G. 
Barbour, W. Burgdorfer, R. Edelman, and R. A. Kaslow, "Spirochetes Isolated 
from the Blood of Two Patients with Lyme Disease," New England J. Med. 
308 (i983):740— 42; A. G. Barbour, W. Burgdorfer, E. Grunwaldt, and A. C. 



344 



Notes to Pages 1^4—^6 



Steere, "Antibodies of Patients with Lyme Disease to Components of the Ixodes 
dammini Spirochete," Journal of Clinical Investigation 72 (i983):504-i5; 
and L. A. MagnarelH, J. F. Anderson, W. Burgdorfer, and W. A. Chappel, 
"Parasitism by Ixodes dammini (Acari: Ixodidae) and Antibodies to Spiro- 
chetes in Mammals and Lyme Disease Foci in Connecticut, USA," /. Med. 
Entomol. 21 (i984):52-57. 

42. M. R. Bovarnik and E. G. Allen, "Reversible Inactivation of Typhus 
Rickettsiae. L Inactivation by Freezing," Gen. Physiol. 38 (i954):i69-79; 
idem, "Reversible Inactivation of Typhus Rickettsiae at o°C," /. Bacteriol. 73 
(1957): 56— 62; idem, "Reversible Inactivation of the Toxicity and Hemolytic 
Activity of Typhus Rickettsiae by Starvation," /. Bacteriol. 74 ( 19 5 7): 637- 
45; W. H. Price, "The Epidemiology of Rocky Mountain Spotted Fever. 
I. The Characterization of Strain Virulence of Rickettsia rickettsii,"" Am. J. 
Hyg. 58 (i953):248-68; W. H. Price, "Variation in 'Rickettsia rickettsii' under 
Natural and Experimental Conditions," in F. W. Hartman, F. L. Horsfall, Jr., 
and I. G. Kidd, eds., Dynamics of Virus and Rickettsial Infections (New York: 
Blakiston Co., 1954), 164-83; J. H. Gilford and W. H. Price, "Virulent- 
Avirulent Conversions of Rickettsia rickettsii in Vitro," Proceedings of the 
National Academy of Sciences 41 (i955):870-73; E. Weiss, H. B. Rees, and 
J. R. Hayes, "Metabolic Activity of Purified Suspensions of Rickettsia rick- 
ettsii,'" Nature 213 (1967): 1020—22. 

43. S. F. Hayes and W. Burgdorfer, "Reactivation of Rickettsia rickettsii in 
Dermacentor andersoni Ticks: An Ultrastructural Analysis," Infect. Immun. 
37 (i982):779— 85. Information about current research on the reactivation 
phenomenon was kindly supplied by David H. Walker in a personal com- 
munication to the author, 30 November 1988. 

44. J. R. Audy, "The Localization of Disease with Special Reference to the 
Zoonoses," Trans. Royal Soc. Trop. Med. Hyg. 52 (i958):3o8— 28 (quotations 
from p. 309); C. A. Hoare, review of E. N. Pavlovsky, P. A. Petrishcheva, 
D. N. Zasukhin, and N. G. Olsufiev, eds.. Natural Nidi of Human Diseases 
and Regional Epidemiology. Proceedings of the Joint Conference of the USSR 
Ministry of Public Health, the USSR Academy of Medical Sciences, the Gam- 
alea Institute of Epidemiology and Microbiology of the USSR Academy of 
Medical Sciences, Dedicated to the Seventieth Anniversary ofE. N. Pavlovsky, 
Member, USSR Academy of Sciences, March z^April i, 19^4 (Leningrad: 
State Publishing House of Medical Literature, 1 9 5 5 ) (in Russian) ; D. Blaskovic, 
ed., Natural Foci of Infectious Diseases. Symposium on Natural Focalization 
of Infections in Man, Animals and Plants, According to the Doctrine of Ac- 
ademician E. N. Pavlovsky (Bratislava: Slovakian Academy of Sciences) (in 
Czech and Slovakian). Historian William H. McNeill has utilized an ecological 
perspective similar to Pavlovsky's in his interpretation of how diseases con- 
tributed to the political and economic ascendency of particular human popula- 
tions. See his Plagues and Peoples (Garden City, N.Y.: Anchor Press/Double- 
day, 1976). 

45. W. Burgdorfer, S. F. Hayes, and A. J. Mavros, "Nonpathogenic Rick- 
ettsiae in Dermacentor andersoni: A Limiting Factor for the Distribution of 
Rickettsia rickettsii" in Burgdorfer and Anacker, eds., Rickettsiae and Rick- 
ettsial Diseases, 585-94 (quotation from p. 585). 

46. Ibid., 592. Robert N. Philip cautions, however, that the interference 
phenomenon may provide only a partial explanation of why R. rickettsii 



Notes to Pages 



345 



appears limited to the west side of the valley. "The phenomenon is probably 
an exceedingly complex one which still remains hypothetical even after eighty 
years of study," he noted in a personal communication to the author, i6 
February 1988. Antigenic interference by nonpathogenic rickettsiae has also 
been noted by Philip and Elizabeth Casper in ticks on the west side of the 
valley. See R. N, Philip and E. A. Casper, "Serotypes of Spotted Fever Group 
Rickettsiae Isolated from D. andersoni (Stiles) Ticks in Western Montana," 
Am. J. Trop. Med. Hyg. 30 (i98i):234-42. 

47. R. R. Parker, "Transmission of Rocky Mountain Spotted Fever by the 
Rabbit Tick Haemaphysalis leporis-plaustris Packard," Am. J. Trop. Med. 3 
(i923):39— 45; R. R. Parker, C. B. Philip, and W. L. Jellison, "Rocky Mountain 
Spotted Fever: Potentialities of Tick Transmission in Relation to Geographical 
Occurrence in the United States," ibid. 13 (i933):34i-79; W, L. Jellison, "The 
Geographical Distribution of Rocky Mountain Spotted Fever and Nuttall's 
Cottontail in the Western United States," Pub. Health Rep. 60 (i945):958- 
61; R. R. Parker, E. G. Pickens, D. B. Lackman, E. J. Bell, and E B. Thrailkill, 
"Isolation and Characterization of Rocky Mountain Spotted Fever Rickettsiae 
from the Rabbit Tick Haemaphysalis leporis-palustris Packard," Pub. Health 
Rep. 66 (i95i):455-63. 

48. W. Burgdorfer, J. C. Cooney, A. J. Mavros, W. L. Jellison, and C. Maser, 
"The Role of Cottontail Rabbits {Sylvilagus spp.) in the Ecology of Rickettsia 
rickettsii in the United States," Am. J. Trop. Med. Hyg. 29 (1980): 68 6-90. 
In a personal communication to the author, 30 November 1988, David H. 
Walker noted: "H. leporis-palustris contains a strain of R. rickettsii called 
HLP. It is genetically closely related to the strains isolated from human cases 
of RMSF but has never been isolated from a human. Robert L. Anacker has 
shown that it has unique surface antigens. Thus there is no evidence that the 
rabbit tick is a vector of the disease. FILP strain may or may not cause any 
disease in humans. It might even be a vaccine candidate. It causes a mild, 
nonfatal disease in guinea pigs." 

49. The term mouse was widely used in early studies to describe rodents 
that are at present termed voles. 

50. W. L. Jellison, "Rocky Mountain Spotted Fever: The Susceptibility of 
Mice," Pub. Health Rep. 49 (i934):363-67; D. J. Gould and M. L. Miesse, 
"Recovery of a Rickettsia of the Spotted Fever Group from Microtus penn- 
sylvanicus from Virginia," Proc. Soc. Exp. Biol. Med. 85 (i954):558-6i; 
W. Burgdorfer, V. F. Newhouse, E. G. Pickens, and D. B. Lackman, "Ecology 
of Rocky Mountain Spotted Fever in Western Montana. I. Isolation of Rick- 
ettsia rickettsii from Wild Mammals," Am. J. Hyg. j6 (i962):293-30i; W. 
Burgdorfer, K. T. Friedhoff, and J. L. Lancaster, Jr., "Natural History of Tick- 
Borne Spotted Fever in the USA: Susceptibility of Small Mammals to Virulent 
Rickettsia rickettsii,'' Bull. WHO 35 (1966): 149-53 ; W. Burgdorfer, "Ecology 
of Tick Vectors of American Spotted Fever," Bull. WHO 40 (i969):375-8i; 
L. A. Magnarelli, J. R Anderson, Willy Burgdorfer, R. N. Philip, and W A. 
Chappell, "Antibodies to Rickettsia rickettsii in Peromyscus leucopus from a 
Focus of Rocky Mountain Spotted Fever in Connecticut," Can. J. Microbiol. 
30 (i984):49i-94. 

51. R. R. Parker, "Rocky Mountain Spotted Fever: Epidemiology with 
Particular Reference to Distribution and Prevalence in the Western United 
States," Northwest Medicine 34 (i935):iii-2i (quotations from p. 114). 



34^ 



Notes to Pages 2j8-jp 



52. F.J. Spencer, "Tick-Borne Disease in Virginia, 1949-195 8: An Ecological 
Note," Am. /. Trop. Med. Hyg. 10 (i96i):220— 22. 

53. V. F. Newhouse, K. Choi, R. C. Holman, S. B. Thacker, L. J. D'Angelo, 
and J. D. Smith, "Rocky Mountain Spotted Fever in Georgia, 1961-75: Anal- 
ysis of Social and Environmental Factors Affecting Occurrence," Pub. Health 
Rep. 1 01 ( 1 98 6) :4 1 9-28; J. E. McDade and V. F. Newhouse, "Natural Flistory 
of Rickettsia rickettsii,'"' Ann. Rev. Microbiol. 40 (i986):287— 309. 



Note on Sources 



In the study of the history of diseases, the quaHty of materials available is 
highly variable, especially when the subject spans a number of centuries. 
Fortunately, the archival record of Rocky Mountain spotted fever, compiled 
essentially within the twentieth century, is especially rich. Most early inves- 
tigators of this disease were meticulous in preserving data, correspondence, 
and scrapbook material. Many of those who have contributed to spotted fever 
research since World War II are still active in the laboratory or are recently 
retired. Although their papers have not yet been accessioned into libraries, a 
number generously agreed to provide oral interviews for this project. In this 
bibliographic essay, I have not attempted an exhaustive Hsting of sources 
consulted. What follows is a discussion of the major categories that attempts 
to provide some indication of their usefulness. 

Histories of Rocky Mountain Spotted Fever 

Aside from medical reviews and official publications of the state of Montana, 
which are discussed below, the earliest survey of Rocky Mountain spotted 
fever is James W. Sampson, "Rocky Mountain Spotted Fever: A Review of 
the Literature with Some Previously Unreported Notes from a Number of 
Wyoming Physicians," senior thesis. University of Nebraska College of Med- 
icine, 1936. This was followed shortly afterward by Ernest L. Berry, "A Study 
of Rocky Mountain Spotted Fever," M.S. in public health thesis. University 
of Michigan, 1940. Both are reviews of the published scientific literature by 
students within the medical establishment. The book that has stood for decades 
as the standard history of spotted fever is Esther Gaskins Price, Fighting Spotted 
Fever in the Rockies (Helena, Mont.: Naegele Printing Co., 1948). A medical 
writer who had previously worked for the Mayo CHnic, Price prepared her 
book for the Montana State Board of Entomology, and it is thus biased toward 
the efforts of that group. Nearly two decades later, Jerry K. Aikawa published 
Rocky Mountain Spotted Fever (Springfield, 111.: Charles C. Thomas, 1966). 
A distinguished rickettsiologist, Aikawa cited Price's book as the major source 
for his historical interpretation but added more material on Howard Taylor 
Ricketts, whom he admired. The goal of Aikawa's book, however, was to 
educate medical students about spotted fever, hence much of the material is 
written in technical language. 

Reviews of Rickettsial Diseases 

In setting Rocky Mountain spotted fever in the context of research on 
rickettsial diseases, one must begin with the classic history of epidemic typhus 
by Hans Zinsser, Rats, Lice, and History (Boston: Little, Brown & Co., 1935). 
This book and Zinsser's As I Remember Him: The Autobiography of R.S. 



347 



348 



Note on Sources 



(Boston: Little, Brown & Co., 1940) provided a lively overview of the role 
of typhus in history and of the personalities of many rickettsial investigators. 
Another invaluable source for a general overview of the field was Nicholas 
Hahon, ed., Selected Papers on the Pathogenic Rickettsiae (Cambridge, Mass.: 
Harvard University Press, 1968). In addition to helpful essays introducing 
each scientific paper, Hahon's book provided English translations of important 
foreign papers. 

The successive editions of Bergey's Manual of Determinative Bacteriology 
(Baltimore: Williams & Wilkins, various dates) also proved an indispensable 
aid and a primary source for charting changes in rickettsial classification and 
nomenclature. Laboratory techniques for diagnosing rickettsial diseases were 
described in Diagnostic Procedures for Viral and Rickettsial Infections (New 
York: American Public Health Association, 1964). Two general textbooks of 
microbiology served as references and sources of general overviews on several 
fields relating to rickettsial research. They are: Bernard D. Davis, Renato 
Dulbecco, Herman N. Eisen, Harold S. Ginsberg, W. Barry Wood, and Maclyn 
McCarty, Microbiology^ zd ed. (New York: Harper 6c Row, 1973); and Gerard 
J. Tortora, Berdell R. Funke, and Christine L. Case, Microbiology: An In- 
troduction, zd ed. (Menlo Park, Calif.: Benjamin/Cummings Publishing Co., 
1986). 

Following the change over time of scientific ideas in rickettsial research was 
facilitated by a series of books. These were: Virus and Rickettsial Diseases, 
with Especial Consideration of Their Public Health Significance, proceedings 
of a symposium. Harvard School of Public Health, 12-17 June 1939 (Cam- 
bridge, Mass.: Harvard University Press, 1940); F. R. Moulton, ed., Rickettsial 
Diseases of Man, proceedings of a symposium of the American Association 
for the Advancement of Science, Boston, 26—28 December 1946 (Washington, 
D.C.: American Association for the Advancement of Science, 1948); Thomas 
M. Rivers, ed.. Viral and Rickettsial Infections of Man, zd ed. (Philadelphia: 
J. B. Lippincott Co., 1952); Thomas M. Rivers and Frank L. Horsfall, Jr., 
eds.. Viral and Rickettsial Infections of Man, 3d ed. (Philadelphia: J. B. Lip- 
pincott Co., 1959); Frank L. Horsfall, Jr. and Igor Tamm, eds. Viral and 
Rickettsial Infections of Man, 4th ed. (Philadelphia: J. B. Lippincott Co., 
1965); Willy Burgdorfer and Robert L. Anacker, eds. Rickettsiae and Rick- 
ettsial Diseases (New York: Academic Press, 198 1). A new book, published 
just as work on this book was being completed, continues this trend. It is 
David H. Walker, ed.. Biology of Rickettsial Diseases, 2 vols. (Boca Raton, 
Fla.: CRC Press, 1988). One additional source, which provided information 
about rickettsial research from the perspective of the Soviet Union, is P. F. 
Zdrodovskii and H. M. Golinevich, The Rickettsial Diseases, trans. B. Haigh 
(New York: Pergamon, i960). 

Histories of the Bitterroot Valley 

Because Rocky Mountain spotted fever is a disease of nature, its well- 
documented history in the Bitterroot Valley of Montana provided an excellent 
case study in how human communities deal with diseases they encounter 
through an unwitting alteration of an area's ecology. Searching for evidence 
of the apparently disease-free ecology of the valley during its occupation by 
the Salish, or Flathead, Indians was facilitated by Peter Ronan, History of the 



Note on Sources 



349 



Flathead Indians (Minneapolis: Ross & Haines, 1890), a record left by an 
Indian agent, and by Reuben G. Thwaites, ed.. The Journals of Lewis and 
Clark, 8 vols. (New York, 1905; reprint. New York: Arno Press, 1969). Because 
of the active interest of Ravalli County citizens in their past, the period after 
white settlement is copiously documented in the archives of the Ravalli County 
Historical Society. Two publications on Bitterroot history were helpful in 
following social, political, and economic developments; curiously, neither men- 
tions Rocky Mountain spotted fever. These are Samuel Lloyd Cappious, "A 
History of the Bitter Root Valley to 19 14," M.A. thesis, University of Wash- 
ington, 1939, and Bitter Root Valley Historical Society, ed., Bitterroot Trails, 
1 vols. (Darby, Mont.: Professional Impressions, 1982). On the history of 
medicine in the Bitterroot and in Montana, Paul C. Phillips, Medicine in the 
Making of Montana (Missoula: Montana State University Press, 1962) is 
essential and contains only minor errors. One document that proved especially 
helpful was Robert N. Philip's study of newspapers, "A Journalistic View of 
Western Montana, 1870— 19 10: Some Newspaper Items Relevant to the De- 
velopment of the Bitter Root Valley and the Occurrence of Rocky Mountain 
Spotted Fever," manuscript, Ravalli County Historical Society, Hamilton, 
Montana, and the University of Montana, Missoula, 1984. With the care of 
an epidemiologist, this study documents land use patterns, population trends, 
transportation and industrial developments, and the broader medical context 
in which evidence regarding Rocky Mountain spotted fever first appeared. 

Manuscripts and Official Publications— Montana 

Two other archival repositories in Montana contained rich records relating 
to Rocky Mountain spotted fever. At the Montana State Archives in Helena, 
the Montana State Board of Health Records, 1908—77, Record Group 28, 
contained not only internal state correspondence about the disease but also 
an abundance of correspondence with Howard Taylor Ricketts, S. Burt Wol- 
bach, and representatives of the U.S. Public Health Service. The Minutes of 
the Montana State Board of Health, 15 March 1907-21 November 1975, on 
microfilm, provided a record of official decisions during the period in which 
spotted fever research was under the aegis of the Montana State Board of 
Health. In addition, the state archives holds a complete collection of the 
monthly reports of the laboratory in Hamilton between the 1920s and World 
War II. Also in their collections are the following useful reports of state boards 
that dealt with spotted fever: Montana State Board of Health, Biennial Reports, 
1 90 1— 13, and Montana State Board of Entomology, Biennial Reports, 19 13— 
3 1 . These published documents, of course, are also available elsewhere. Because 
Robert A. Cooley, who served as secretary of the Montana State Board of 
Entomology from 1913 to 1931, spent his academic career at the institution 
now called Montana State University in Bozeman, it also houses materials 
important to the history of spotted fever. They are a part of the Zoology and 
Entomology Archives in the Renne Library and contain significant information 
from the 1920s through the 1940s about spotted fever work in Hamilton. 

At the Rocky Mountain Laboratories (RML) of the National Institute of 
Allergy and Infectious Diseases (NIAID), a number of key documents relating 
to early spotted fever research had for years been preserved as a part of its 
institutional memory. Concerned about the security of these materials and 



350 



Note on Sources 



their availability to other scholars, NIAID administrators requested that they 
be evaluated and placed in appropriate archival repositories. Of those ma- 
terials, two collections generated when the state of Montana was in charge 
of investigations were transferred to the Montana State Archives. They were 
the seventeen bound volumes of the correspondence of Robert A. Cooley 
during his tenure as secretary of the Montana State Board of Entomology and 
one bound typescript volume of the Minutes of the Montana State Board of 
Entomology. Both, of course, are a mine of information on spotted fever and 
should be useful also to scholars interested in the history of entomology. The 
disposition of additional RML materials relating to the period of federal 
support of spotted fever research is discussed below. 

Manuscript Materials— Federal Government 

U.S. Public Health Service investigations of spotted fever commenced in 
1902, and the Records of the Public Health Service, held in Record Group 
90 at the National Archives and Records Administration, Washington, D.C., 
contain much material between that date and World War II. In addition, federal 
records long stored at the RML have been added to the spotted fever holdings 
of the National Archives, accessioned as Research Records of the Rocky 
Mountain Laboratory, Records of the National Institutes of Health, Record 
Group 443. These include correspondence files of early investigators; and the 
notebooks of case records by state and year prepared by Ralph R. Parker. In 
addition to information on Rocky Mountain spotted fever, a number of these 
notebooks document other arthropod-borne diseases, such as tularemia and 
Q fever, and one contains the transcript of a conference on post World War 
II plans for research. 

Many materials remaining at the RML were also invaluable to this history. 
Copies of the Rocky Mountain Laboratory Annual Reports were essential. 
Robert K. Bergman, chief of the Rocky Mountain Operations Branch, NIAID, 
also permitted me to examine files known as the "director's office files," which 
provided much background information on the history of the laboratory. A 
collection of seven scrapbooks that covered the period 1919-60 contained 
much material that did not appear in official reports and was especially useful 
for following news accounts of the work outside Montana. Laboratory pho- 
tographer Nick Kramis rendered the historian a great service when he prepared 
an index to his large collection of photographs, both of which are held at the 
RML. 

The collections of the History of Medicine Division of the National Library 
of Medicine (NLM) in Bethesda, Maryland, contain U.S. Public Health Service 
scrapbooks of clippings on diseases and on the work of the service, 1876— 
1914, as well as U.S. Hygienic Laboratory Registers, 1901-23. The library's 
large number of oral histories provide personal perspectives on the develop- 
ment of medical research, especially within the federal government. 

The active files of NIAID, both in Bethesda, Maryland, and at the RML in 
Hamilton, Montana, contain materials documenting the history of the institute 
and its predecessor organizations in spotted fever research. The Minutes of 
the Board of Scientific Counselors of the National Institute of Allergy and 
Infectious Diseases, 1955-81, for example, record the deliberations of this 
policy advisory board of nonfederal scientists. Recommendations of this board 



Note on Sources 



351 



helped to explain the changing focus of institute research priorities in recent 
decades. The files of the NIAID Microbiolog}- and Infectious Diseases Program, 
moreover, contain material on the mid-1970s withdrawal of the military ser- 
vices from Rocky Mountain spotted fever research and its assumption in toto 
by NIAID. William Jordan, director of the program, and Robert Edelman, 
chief of its Clinical Studies Branch, kindly made these files available. The 
institute's PubUc Information Office also contains some historical materials, 
and, in the course of this project, I collected a vertical file of information and 
correspondence now held in the NIH Historical Office. 

Other Manuscript Collections 

The papers of Howard Taylor Ricketts, held in the Department of Special 
Collections, Joseph Regenstein Library, University of Chicago, proved to be 
a rich source of information about his research. A scrapbook, prepared by 
his family and deposited in selected libraries, reproduces selected papers from 
the larger collection and serves as a useful introduction to Ricketts's work. 
After his death in 19 10, his associates in Chicago published a collection of 
scientific papers relating to his work as Howard T. Ricketts, Contributions to 
Medical Science by Howard Taylor Ricketts, i8jo-ipio (Chicago: University 
of Chicago Press, 191 1). Copies of Ricketts's correspondence and reprints of 
his scientific papers appear in several of these collections, as well as in the 
records of the Montana State Board of Health. To save space, I have not 
attempted to cite multiple sources for each document. 

The Hideyo Noguchi Papers, located in Record Group 210.3, Rockefeller 
University Archives, New York, contain little correspondence about Noguchi's 
spotted fever research. They were useful, however, for providing information 
about the laboratory-acquired infection of Noguchi's assistant, Stephen Mol- 
inseck, and the impact of his disease on acceptance of a rickettsial organism 
as the etiological agent of spotted fever. 

Other collections of papers on major spotted fever researchers did not prove 
so useful. The Louis B. Wilson Papers at the Mayo Clinic, unfortunately, do 
not include manuscript materials relating to his spotted fever work. S. Burt 
Wolbach's spotted fever correspondence is well documented in the Montana 
State Board of Health Records, mentioned above. His papers at the Francis 
A. Countway Library, Harvard University Medical School, Boston, however, 
would provide a rich source for the scholar interested in epidemic t\'phus. 

Published Sources Relating to Federal Research 

For background information on the history of the U.S. Pubhc Health Service, 
Ralph C. Williams, The United States Public Health Service, ij^S-i^^o 
(Washington, D.C.: Commissioned Officers Association, 195 1) is the essential 
starting point. My own book. Inventing the NIH: Federal Biomedical Research 
Policy, i88j—i^^y (Baltimore: Johns Hopkins Universit>' Press, 1986), traces 
the emergence of medical research within the larger framework of the U.S. 
Public Health Service. For the post-World War II period, Charles V. Kidd's 
American Universities and Federal Research (Cambridge, Mass.: Belknap 
Press, 1959) is helpful in following the change in research priorities. His 1957 
manuscript by the same title, on which his book was based, contains additional 



35^ 



Note on Sources 



information and tables. It is available in the National Institutes of Health 
(NIH) Historical Office. 

Other official sources for federal information include: the Annual Reports 
of the Surgeon General of the U.S. Public Health Service and its predecessor 
agencies; U.S. Congressional Record, House of Representatives and Senate; 
and U.S. Statutes at Large. An overview of the major lines of infectious disease 
research conducted by NIAID and its predecessors is provided in National 
Institute of Allergy and Infectious Diseases, Intramural Contributions, i88y— 
198 ed. Harriet R. Greenwald and Victoria A. Harden (Bethesda, Md.: 
National Institute of Allergy and Infectious Diseases, 1987). In addition, ref- 
erence information on budgets, personnel, and leadership within the NIH may 
be quickly accessed through the National Institutes of Health, NIH Almanac, 
published annually (Washington, D.C.: U.S. Department of Health and Human 
Services). 

More detailed data about NIH funding for rickettsial disease research pro- 
jects is available through yearly grants publications. From 1948 to 1961, titles 
vary slightly and types of summary data change. The first, covering the period 
1946 (when the grants program began) to 1949, is U.S. National Institutes 
of Health, Division of Research Grants, Research Grants Awarded by the 
Public Health Service, comp. David E. Price, suppl. 205 to the Public Health 
Reports, rev. 1948, addendum 1949. The 1948 revision of this publication 
also includes National Cancer Institute grants dating from 1937. In 1961 the 
first edition of a new format that continued through 1971 was issued. With 
changing years, this is idem. Research Grants Index, Fiscal Year 1961 (Wash- 
ington, D.C.: Government Printing Office). Beginning in 1972, this information 
was stored in a data base at the Division of Research Grants, NIH. Information 
on grants after 197 1 came from a search of this data base for the descriptor 
"Rocky Mountain spotted fever and other rickettsial diseases." 

Bibliographic and Periodical Sources 

In the beginning of a search of the periodical literature, the tools available 
through the NLM are indispensable. The volumes of Index Medicus provide 
not only lists of the scientific papers on spotted fever but also a good indication 
of how the medical concept of the disease changed over time, as indicated by 
different headings under which entries were filed. Most papers published since 
1966 may be accessed through computer data bases on the MEDLARS system 
supported by NLM. Research in the history of medicine is catalogued in the 
library's Bibliography of the History of Medicine, with papers published since 
1970 also indexed in the data base HISTLINE. Especially useful in this project 
were such medical journals of record as the Journal of the American Medical 
Association, indexed separately, and Science, because they contained a wealth 
of editorial, news, bibliographic, and international information in addition to 
reports on clinical and laboratory research findings. 

For amplifying and cross-checking sources, the bibliographies in early re- 
search papers and in later review papers were most useful. In 1954, David G. 
Cooman prepared the Bibliography on the Rocky Mountain Spotted Fever 
Group ofRickettsioses, which is available at NLM, for the U.S. Army Chemical 
Corps Technical Library. Information on rickettsial diseases in Africa can be 
accessed through K. David Patterson, comp., Infectious Diseases in Twentieth- 



Note on Sources 



353 



Century Africa: A Bibliography of Their Distribution and Consequences (Wal- 
tham, Mass.: African Studies Association, Crossroads Press, 1979), especially 
"Typhus and Other Rickettsial Infections," 195-98. Publications about ticks 
and tick-borne diseases are indexed in Harry Hoogstraal, Bibliography of 
Ticks and Tickborne Diseases from Homer (about 800 B.C.) to 31 December 
1969, 5 vols. (Cairo: U.S. Naval Medical Research Unit No. 3, 1970). The 
Reader's Guide to Periodical Literature provided an index to the popular 
literature on spotted fever and on attitudes toward medicine in general in the 
United States. The New York Times Index similarly served as a source from 
which societal response to disease could be followed over time. 

Biographical Information 

Many sources proved useful for biographical information on key figures in 
the history of spotted fever. Jeanette Barry, comp., Notable Contributions to 
Medical Research by Public Health Service Scientists: A Bibliography to 1940 
(Washington, D.C.: Government Printing Office, i960) summarized biograph- 
ical and bibliographical information about the most notable federal scientists. 
The personnel files of deceased U.S. Public Health Service officers, located at 
the Federal Records Center in Saint Louis, Missouri, provided information 
not only about the leaders of federal research, but also about those who never 
achieved fame. I am indebted to the Commissioned Officers Corps staff in 
Rockville, Maryland, for helping me obtain copies of these records. Elizabeth 
Moot O'Hearn, Profiles of Pioneer Women Scientists (Washington, D.C.: 
AcropoHs Books, 1985) is useful for women investigators, and Paul F. Clark, 
Pioneer Microbiologists of America (Madison: University of Wisconsin Press, 
1961) contains many helpful sketches. The Library and Information Man- 
agement Section of the American Medical Association kindly provided infor- 
mation about several early spotted fever investigators and public health figures 
who were not documented in published sources. Other major biographical 
tools included various editions of American Men of Science and American 
Men and Women of Science (editors and other details of publication vary; 
information for the relevant edition is supplied in the notes); Charles Coulston 
Gillispie, ed.. Dictionary of Scientific Biography^ 16 vols. (New York: Charles 
Scribner's Sons, 1970—80); Dictionary of American Biography, 2.0 vols., 6 
suppls. (New York: Charles Scribner's Sons, 1932-80); Who's Who in America 
(Chicago: Marquis— Who's Who, various editions); Allen G. Debus, ed.. World 
Who's Who in Science: A Biographical Dictionary of Notable Scientists from 
Antiquity to the Present, (Chicago: Marquis-Who's Who, 1968). There is, 
unfortunately, a paucity of biographical information about foreign scientists. 
Biographical dictionaries for British and German investigators are available, 
but it is often impossible to locate first names, let alone background infor- 
mation, on many other European, Latin American, and Japanese researchers. 

Oral Histories and Interviews 

For personal assessments of twentieth-century medical research, the oral 
histories in the NLM provide an excellent starting point. During the 1960s, 
Harlan Phillips conducted a number of oral histories that are catalogued as 
George Rosen, "Transcripts of Oral History Project, 1962-1964," Manu- 



354 



Note on Sources 



scripts Collection, History of Medicine Division, NLM. Among those inter- 
viewed in this series are Roscoe R. Spencer, Rolla Eugene Dyer, Norman H. 
Topping, and Victor H. Haas. Phillips also conducted an extensive oral history 
project with. Stanhope Bayne-Jones, director of the U.S.A. Typhus Commission. 
Its five volumes are indexed separately at NLM. In addition, former NIH and 
NLM historian Wyndham Miles interviewed a number of NIH administrators. 
These interviews are now catalogued and augment the already large collection. 

During the course of my research, I conducted short interviews with many 
scientists connected with the RML and the NIH. These are available in the 
NIAID files, NIH Historical Office. Those interviews related to research for 
this book were with Robert L. Anacker, E. John Bell, J. Frederick Bell, Willy 
Burgdorfer, Dorland J. Davis, Victor H. Haas, William L. Jellison, Nick 
Kramis, David B. Lackman, Richard A. Ormsbee, Cornelius B. Philip, and 
Robert N. Philip. 

Conversations and Correspondence 

As my thinking about the ideas in this book took shape, a number of people 
generously offered suggestions, criticism, encouragement, and advice. Among 
my historian colleagues, thanks are due to James Harvey Young, Charles 
Howard Candler Professor Emeritus at Emory University; Saul Benison of the 
University of Cincinnati; Robert J. T. Joy of the Uniformed Services University 
of the Health Sciences; Suzanne White of the U.S. Food and Drug Adminis- 
tration; Caroline Hannaway and Kimberly Pelis of the Institute of the History 
of Medicine, Johns Hopkins University School of Medicine. Ruth Levy Guyer, 
formerly at NIAID and now on the staff of Science^ patiently introduced me 
to immunology. James Kerians, curator of the tick collection formerly at the